Microemulsion Topical Delivery Platform

ABSTRACT

Provided are pharmaceutical carriers suitable based on oil-in-water microemulsions and methods of making same. Also provided are pharmaceutical compositions comprising a carrier of the invention and a lipophilic active pharmaceutical ingredient (API), as well as methods for making same. The pharmaceutical compositions are particularly suitable for use in formulating lipophilic APIs for topical administration to the eye. Specifically included are pharmaceutical compositions comprising fenofibrate or fenofibric acid as API. Also provided is a method of treating a disease of the posterior segment of the eye. Also provided is a pharmaceutical composition comprising a compound represented by 
     
       
         
         
             
             
         
       
     
     formulated for topical administration to the eye.

RELATED APPLICATION

This application claims benefit of U.S. Provisional Patent ApplicationNo. 61/784,005, filed Mar. 14, 2013.

BACKGROUND OF THE INVENTION

Delivery of active pharmaceutical ingredients (APIs) to the eye may beachieved most conveniently by topical administration to the eye.However, topical delivery of APIs to the eye is commonly limited by anumber of factors, including low residence time, poor penetration anddelivery to target tissue, and physiological barriers to delivery. Theselimiting factors are particularly significant for diseases affecting theposterior segment of the eye, and for this reason it is common to resortto other routes of administration, e.g., intraocular (intravitreal)injection and systemic administration, to deliver APIs to the posteriorsegment of the eye.

Of course, intravitreal injection is invasive and requires highlyspecialized conditions including performance by an ophthalmologist in anoperating room. Moreover, intravitreal injection carries attendant risksof infection and, in the case of intravitreal inserts, displacement.

On the other hand, systemic administration, e.g., intravenous injection,while less demanding technically, is subject to physiologic barriers tosuccess. For example, the blood-retina barrier (BRB), like theblood-brain barrier (BBB), limits APIs from reaching the interior of theeye. Moreover, systemic administration may require unacceptably highdosages of API in order to achieve efficacious drug levels within theeye.

Microemulsions are thermodynamically stable and isotropic formulationscomposed of a polar phase (e.g., water), a non-polar phase (e.g., oil),surfactant, and co-surfactant. Unlike nanoemulsions, microemulsions formwithout the need for input energy; they form essentially spontaneously.Certain microemulsions, characterized by their clarity, stability, andthe possibility of sterilization, represent candidate topical deliveryplatforms for APIs directed to the eye.

The eye is divided into two anatomical compartments, called the anteriorchamber and the posterior chamber. The smaller anterior chamber includesall structures including and anterior to the lens, e.g., the cornea,aqueous humor, iris, and the lens. The much larger posterior segmentincludes all remaining structures, i.e., all structures posterior to thelens. These structures include, inter alia, the vitreous humor, retina,retinal blood vessels, macula, choroid, part of the sclera, and opticnerve.

SUMMARY OF THE INVENTION

The invention concerns specific formulations of, and methods of making,microemulsions and microemulsion formulations which useful aspharmaceutical carriers. In a broad sense, the microemulsions andmicroemulsion formulations may be used for topical delivery of activepharmaceutical ingredients, particularly lipophilic APIs, to any tissue.It has been found, for example, that microemulsions and microemulsionformulations of the invention are suitable for deliveringtherapeutically meaningful amounts of certain APIs to internalstructures of the eye. The microemulsions and microemulsion formulationsof the invention are suitable for topical administration to the eye, forexample in the form of eyedrops. Surprisingly, topical delivery ofmicroemulsion formulations according to the invention is effective totreat even diseases of the posterior segment of the eye.

An aspect of the invention is a pharmaceutical carrier suitable fortopical administration to the eye, comprising:

an oil-in-water microemulsion comprising

(i) an oil selected from the group consisting of isopropyl myristate,isopropyl palmitate, and medium chain triglycerides;

(ii) a pair of surfactants selected from the group consisting of twopolysorbates, a polysorbate and propylene glycol, a polysorbate andglycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane),cremophor EL (polyethoxylated castor oil) and triacetin(1,2,3-triacetoxypropane), and cremophor EL (polyethoxylated castor oil)and propylene glycol; and

(iii) water,

wherein:

the water represents 50 to about 95 percent (w/w) of the pharmaceuticalcarrier;

the oil and surfactants represent substantially all of the remainder ofthe pharmaceutical carrier; and

the ratio of percent (w/w) total surfactant to percent (w/w) oil is atleast about 10:1.

An aspect of the invention is a method of making the pharmaceuticalcarrier of the invention. The method comprises the steps of combiningthe oil and the pair of surfactants, to yield an oil/surfactant mixture;and combining the oil/surfactant mixture with the water.

An aspect of the invention is a pharmaceutical composition, comprising alipophilic active pharmaceutical ingredient (API) and the pharmaceuticalcarrier of the invention, wherein the pharmaceutical composition isformulated for topical administration to the eye.

An aspect of the invention is a method of making the pharmaceuticalcomposition of the invention. The method comprises the steps ofcombining the oil, the pair of surfactants, and the lipophilic activepharmaceutical ingredient (API), to yield an oil/surfactant/API mixture;and combining the oil/surfactant/API mixture with the water.

An aspect of the invention is method of treating a disease of theposterior segment of the eye. The method comprises the step of topicallyadministering to an eye of a subject in need thereof a compositioncomprising:

an oil-in-water microemulsion comprising

(i) an oil selected from the group consisting of isopropyl myristate,isopropyl palmitate, and medium chain triglycerides;

(ii) a pair of surfactants selected from the group consisting of twopolysorbates, a polysorbate and propylene glycol, a polysorbate andglycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane),cremophor EL (polyethoxylated castor oil) and triacetin(1,2,3-triacetoxypropane), and cremophor EL (polyethoxylated castor oil)and propylene glycol;

(iii) water; and

(iv) a therapeutically effective amount, for treating a disease of theposterior segment of the eye, of a lipophilic active pharmaceuticalingredient (API),

wherein:

the API represents about 0.01 to about 5 percent (w/v) of thecomposition;

the water represents 50 to about 95 percent (w/w) of the composition;

the oil and surfactants represent substantially all of the remainder ofthe composition;

the ratio of percent (w/w) total surfactant to percent (w/w) oil is atleast about 10:1;

and

the composition is formulated for topical administration to the eye.

In one embodiment, the API is represented by

In one embodiment, the disease of the posterior segment of the eye ischaracterized by inflammation, neovascularization, vascular leakage,fibrosis, or any combination thereof.

In one embodiment, the disease of the posterior segment of the eye isselected from the group consisting of: age-related macular degeneration,diabetic retinopathy, posterior uveitis, retinal edema, macular edema,and retinal vein occlusion.

In one embodiment, the disease of the posterior segment of the eye isage-related macular degeneration.

In one embodiment, the disease of the posterior segment of the eye isdiabetic retinopathy.

An aspect of the invention is pharmaceutical composition, comprising aneffective amount, for treating a disease of the posterior segment of theeye, of a compound represented by

and the pharmaceutical carrier of the invention, wherein thepharmaceutical composition is formulated for topical administration tothe eye.

In one embodiment, the pharmaceutical composition is formulated aseyedrops.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a pair of photographic images of a single series of twentyclear glass vials containing various formulations of water, oil, andsurfactant; and a map representing the formulations in the vials. Thevial at the left of the upper photo corresponds to map position A1, andsuccessive vials to the right correspond to map positions A2, A3, etc.The vial at the left of the lower photo corresponds to map position B1,and successive vials to the right correspond to map positions B2, B3,etc. Vial A1 contains (i) 500 μL of oil phase comprised of 90 percent3:1 Cremophor EL:propylene glycol surfactant/co-surfactant mixture/10percent isopropyl myristate, and (ii) 500 μL water. Vial A2 comprises(i) 475 μL of the same oil phase, and (ii) 525 μL water. This successivedilution continues until reaching vial B10, which comprises (i) 25 μL ofthe same oil phase, and (ii) 975 μL water. Clear formulations representmicroemulsions.

FIG. 2 is a representative pseudoternary phase diagram with 100 percentwater, 100 percent oil, and 100 percent total surfactant at the apiceslabeled Water, Oil, and Surfactant, respectively. The area enclosed byheavier lines represents potential oil-in-water microemulsion space(water >50 percent). Each symbol represents a data point for actualcombinations of different water/oil/total surfactant combinations testedin the Examples. (Microemulsions correspond to only a subset of thesepoints.)

FIG. 3 is a graph depicting quantification of MSH-1001 in rabbit aqueoushumor measured 1 hour after topical administration to the eye. X axisshows percent (w/v) of drug in individual emulsion formulations. ED-007to ED-017 are microemulsions; ED-002 is a nanoemulsion. AH=aqueoushumor; IPM=isopropyl myristate.

FIG. 4 is a whisker plot graph depicting microemulsion sizedistribution. Higher and lower extremes represent the d90 and d10droplet sizes, respectively.

FIG. 5 is a whisker plot graph depicting microemulsion sizedistribution. Higher and lower extremes represent the d90 and d10droplet sizes, respectively. Data is shown in pairs for values measuredon Day 1 and Day 14 for each microemulsion.

FIG. 6 is whisker plot graph depicting microemulsion size distributionfor MEM0043 at Days 1, 14, and 379.

FIG. 7 is a pair of bar graphs depicting concentrations of fenobrate andfenofibric acid in retina (left panel) and retinal pigment epithelium(RPE) (right panel) of rabbits, as measured by LC/MS, following QID×5days eye drop administration to eyes of fenofibrate formulated as 0.5%fenofibrate in the indicated microemulsions (MEM0043 and MEM0044) or 3%fenofibrate in the indicated nanoemulsions (NEM 001 and NEM 002).

FIG. 8 is a bar graph depicting lesion size measured in rats wherechoroidal neovascularization was induced by laser. Rats were treated QIDfor 19 consecutive days with either vehicle alone or fenofibrateformulated as 3% fenofibrate in nanoemulsion (NEM-001) or 0.5%fenofibrate in microemulsion (MEM-0043). *** p<0.001 compared tovehicle.

DETAILED DESCRIPTION

As described herein, Applicant has identified, through exhaustivetrial-and-error analysis of many combinations of possible components, agroup of microemulsion formulations particularly well suited for use intopical administration of lipophilic drugs, including, in particular,for ophthalmic use. The microemulsion formulations are clear, stable,well tolerated, and capable of delivering therapeutically effectiveamounts of active pharmaceutical ingredients to target sites, includingsites within the eye. Surprisingly, the microemulsion formulations ofthe invention are capable of delivering therapeutically effectiveamounts of active pharmaceutical ingredients to the posterior segment ofthe eye following topical administration to the eye.

An aspect of the invention is a pharmaceutical carrier suitable fortopical administration to the eye, comprising:

an oil-in-water microemulsion comprising

(i) an oil selected from the group consisting of isopropyl myristate,isopropyl palmitate, medium chain triglycerides, and any combinationthereof;

(ii) a pair of surfactants selected from the group consisting of twopolysorbates, a polysorbate and propylene glycol, a polysorbate andglycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane),cremophor EL (polyethoxylated castor oil) and triacetin(1,2,3-triacetoxypropane), and cremophor EL (polyethoxylated castor oil)and propylene glycol; and

(iii) water,

wherein:

the water represents 50 to about 95 percent (w/w) of the pharmaceuticalcarrier;

the oil and surfactants represent substantially all of the remainder ofthe pharmaceutical carrier; and

the ratio of percent (w/w) total surfactant to percent (w/w) oil is atleast about 10:1.

As used herein, an “oil-in-water microemulsion” is a microemulsioncomprised of at least 50 percent (w/w) water, at least one organicchemical that is normally at least substantially immiscible in water(i.e., an oil), and at least two surfactants (sometimes referred to assurfactant and co-surfactant). The dispersed oil phase is dispersed asdroplets in the continuous (water) phase, where the droplets typicallyhave a mean diameter of less than about 300 nm, e.g., about 5 nm toabout 200 nm. A microemulsion characteristically has a clear ortranslucent appearance on visual inspection because the droplets are toosmall to scatter light of visible wavelengths. Microemulsions typicallyhave viscosities lower than liquid crystals, e.g., about 10-400 mPa·s.

As used herein, “medium chain triglyceride” or “MCT” refers totriglyceride for which at least 90 percent of fatty acids are made of8-10 carbon atoms. Examples include Myglyol® 810 or 812 (triesters ofglycerol, capric acid, and caprylic acid; Sasol Germany GmbH, Witten,Germany) and oils obtained by hydrolysis, fractionation, andesterification of coconut oil. Bach, A et al. (1982) Am J Clin Nutr36:293. MCTs are more water-soluble than long-chain triglycerides, yetthey accommodate large amounts of lipophilic drugs.

As used herein, the term “surfactant” takes its usual meaning, and a“pair of surfactants” refers to two surfactants or, equivalently, asurfactant and a co-surfactant. The two surfactants can be present inthe same or different amounts.

As used herein, the term “polysorbate” refers generally to apolyoxyethylene derivative of sorbitan fatty acid ester. Commoncommercial preparations of polysorbates are sold under the name Tween®,Alkest, or Canarcel. In the nomenclature of polysorbates, the numericdesignation following polysorbate (or Tween®) refers to the lipophilicgroup. For example, polysorbate 20 is a monolaurate ester, andpolysorbate 80 is a monooleate ester.

Cremophor® EL (BASF SE), is a version of polyethoxylated castor oil, themajor component of which is glycerol polyethylene glycol ricinoleate.Additional components include free polyethylene glycols and ethoxylatedglycerol. It is prepared by reacting 35 moles of ethylene oxide witheach mole of castor oil. The product has been given CAS number61791-12-6.

In one embodiment, the water represents 50 percent (w/w) of thepharmaceutical carrier.

In one embodiment, the water represents at least about 55 percent (w/w)of the pharmaceutical carrier.

In one embodiment, the water represents at least about 60 percent (w/w)of the pharmaceutical carrier.

In one embodiment, the water represents at least about 65 percent (w/w)of the pharmaceutical carrier.

In one embodiment, the water represents at least about 70 percent (w/w)of the pharmaceutical carrier.

In one embodiment, the water represents at least about 75 percent (w/w)of the pharmaceutical carrier.

In one embodiment, the water represents at least about 80 percent (w/w)of the pharmaceutical carrier.

In one embodiment, the water represents at least about 85 percent (w/w)of the pharmaceutical carrier.

In one embodiment, the water represents at least about 90 percent (w/w)of the pharmaceutical carrier.

The term “w/w” as used herein means ratio of weight of component (ingrams) to weight of solution (in grams), where weight of solution refersto the total weight of the oil, water, and surfactant. As an example, 1percent (w/w) isopropyl myristate denotes 1 g isopropyl myristate per100 g total weight.

The term “w/v” as used herein means ratio of weight (in grams) to volume(in mL), where volume refers to the final volume. As an example, 1percent (w/v) isopropyl myristate denotes 1 g isopropyl myristate per100 mL final volume.

As used herein in connection with any particular numerical value, in oneembodiment the term “about” means that particular numerical value plusor minus 5% of that particular value. Thus, for example, the term “about1 percent (w/w)” can be understood to embrace a range of values from0.95 to 1.05 percent (w/w). Similarly, the term “about 10:1” can beunderstood to embrace a range of values from 9.5:1 to 10.5:1.

Moreover, the term “at least about 10:1” in one embodiment means fromabout 10:1 to about 20:1. In additional separate embodiments, the term“at least about 10:1” means from about 10:1 to about 11:1; from about10:1 to about 12:1; from about 10:1 to about 13:1; from about 10:1 toabout 14:1; and from about 10:1 to about 15:1.

In one embodiment, the term “at least about 10:1” means about 10:1.

In one embodiment, the oil is isopropyl myristate.

In one embodiment, the oil is isopropyl palmitate.

In one embodiment, the oil is medium chain triglycerides.

In one embodiment, the pair of surfactants is two polysorbates. Forexample, in one embodiment, the pair of surfactants is polysorbate 20and polysorbate 80.

In one embodiment, the pair of surfactants is a polysorbate andpropylene glycol.

In one embodiment, the pair of surfactants is a polysorbate andglycerol.

In one embodiment, the pair of surfactants is a polysorbate andtriacetin (1,2,3-triacetoxypropane).

In one embodiment, the pair of surfactants is cremophor EL(polyethoxylated castor oil) and triacetin (1,2,3-triacetoxypropane).

In one embodiment, the pair of surfactants is cremophor EL(polyethoxylated castor oil) and propylene glycol.

An aspect of the invention is a method of making the pharmaceuticalcarrier just described above, i.e., a method of making thepharmaceutical carrier of the invention. The method includes the stepsof combining the oil and the pair of surfactants, to yield anoil/surfactant mixture; and combining the oil/surfactant mixture withthe water. The combined components will form a microemulsion essentiallyspontaneously. That is, thorough mixing alone, for example by rocking orgentle vortexing, sufficient to bring all components into contact,should suffice to form the microemulsion.

Preferred microemulsions are optically clear and homogeneous to visualinspection, and thermodynamically stable.

The method of making the pharmaceutical carrier optionally can includethe further step of sterilizing the formed pharmaceutical carrier, forexample by sterile filtering or autoclaving for 20 min at 121° C.

The method of making the pharmaceutical carrier optionally can includethe further step of sizing the droplets.

An aspect of the invention is a pharmaceutical composition, comprising alipophilic active pharmaceutical ingredient (API) and the pharmaceuticalcarrier of the invention, wherein the pharmaceutical composition isformulated for topical administration to the eye.

The API can be any lipophilic API. As used herein, the term “lipophilic”means substantially more soluble in lipid, oil, or fat than in water atroom temperature. In one embodiment, the term “lipophilic” further meanshaving a solubility in water at room temperature of less than or equalto 30 mg/mL. In one embodiment, the term “lipophilic” further meanshaving a solubility in water at room temperature of less than or equalto 10 mg/mL. In one embodiment, the term “lipophilic” further meanshaving a solubility in water at room temperature of less than or equalto 1 mg/mL. In one embodiment, the term “lipophilic” further meanshaving a solubility in water at room temperature of less than or equalto 0.5 mg/mL. In one embodiment, the term “lipophilic” further meanshaving a solubility in water at room temperature of less than or equalto 0.2 mg/mL. In one embodiment, the term “lipophilic” further meanshaving a solubility in water at room temperature of less than or equalto 0.1 mg/mL. In one embodiment, the term “lipophilic” further meansnegligibly soluble in water at room temperature.

In one embodiment, the lipophilic API is selected from the groupconsisting of anti-inflammatory agents, anti-infective agents,anti-allergic agents, antihistamines, antiproliferative agents,anti-angiogenic agents, anti-oxidants, antihypertensive agents,neuroprotective agents, cell receptor agonists, cell receptorantagonists, immunomodulating agents, immunosuppressive agents,intraocular pressure lowering agents, α2-adrenergic receptor agonists,β1-adrenergic receptor antagonists, carbonic anhydrase inhibitors,cholinesterase inhibitor miotics, prostaglandins, prostaglandin receptoragonists, mast cell degranulation inhibitors (mast cell stabilizers),thromboxane A2 mimetics, protein kinase inhibitors, prostaglandin Fderivatives, prostaglandin F_(2α) receptor antagonists, cyclooxygenase-2inhibitors, muscarinic agents, and any combination thereof.

In one embodiment, the lipophilic API is selected from the groupconsisting of adaprolol maleate, cyclosporine A, fenofibrate, fenofibricacid, indomethacin, miconazole, pilocarpine, piroxicam, and Δ⁸-THC.

In one embodiment, the lipophilic API is fenofibrate

In one embodiment, the lipophilic API is fenofibric acid.

In one embodiment, the lipophilic API is an API that is useful for thetreatment of a disease of anterior segment of the eye.

A “disease of the anterior segment of the eye” refers to any disease ofthe anterior segment of the eye. Examples of diseases of the anteriorsegment of the eye include, without limitation, cataract, cornealneovascularization, dry eye (keratoconjunctivitis sicca), Fuchs'dystrophy, glaucoma, keratitis (including herpes keratitis), andkeratoconus. In one embodiment, a disease of the anterior segment of theeye specifically excludes diseases of the lens, e.g., cataract. In oneembodiment, a disease of the anterior segment of the eye is glaucoma.

In one embodiment, the API is an API that is useful for the treatment ofa disease of the posterior segment of the eye.

As used herein, the term “posterior segment of the eye” takes its usualmeaning and refers to that part of the eye bounded anteriorly by thelens and anterior hyaloid membrane, and extending to the back of theeye. It is much larger than the anterior segment and includes thevitreous humor, retina, retinal blood vessels, macula, choroid, andoptic nerve.

A “disease of the posterior segment of the eye” refers to any disease ofthe posterior segment of the eye. Of particular interest areinflammatory, autoimmune, vascular, and certain infectious diseases ofthe posterior segment of the eye. Diseases of the posterior segment ofthe eye specifically include, without limitation, age-related maculardegeneration (AMD), diabetic retinopathy, posterior uveitis, retinaledema, macular edema, and retinal vein occlusion. AMD specificallyincludes both dry AMD and wet AMD. Each of these diseases or conditionsis well known in the art and need not be further described here.

In one embodiment, the disease of the posterior segment of the eye ischaracterized by inflammation, neovascularization, vascular leakage,fibrosis, or any combination thereof.

In one embodiment, the disease of the posterior segment of the eye isselected from the group consisting of: age-related macular degeneration,diabetic retinopathy, posterior uveitis, retinal edema, macular edema,and retinal vein occlusion.

As used herein, “topical administration” refers to localizedadministering to a surface of a tissue. Topical administration to theeye refers to localized administering to a surface of an eye, forexample, to any exterior aspect of the eye normally accessible betweenthe eyelids. Topical administration to the eye generally may beachieved, for example, with drops, irrigants, ointments, or sprays.

In one embodiment, the pharmaceutical composition of the invention isformulated as eyedrops. For example, the composition may be presented ina rigid bottle fitted with a combination screw-cap/bulb pipette droppercap. In one embodiment the composition is presented in a squeeze bottlefitted with a tip constructed and arranged to serve as a dropper and aremovable cap to cover the tip. In a typical embodiment the eyedrops aredispensed as 30 microliter to 300 microliter single drops.

An aspect of the invention is method of making the pharmaceuticalcomposition just described. The method includes the steps of combiningthe oil, the pair of surfactants, and the lipophilic activepharmaceutical ingredient (API), to yield an oil/surfactant/API mixture;and combining the oil/surfactant/API mixture with the water.

The API is included in the pharmaceutical composition in atherapeutically effective amount to treat a particular disease that isto be treated using the pharmaceutical composition.

As used herein, a “therapeutically effective amount” is any amount thatis sufficient to achieve a desired therapeutic result. For example, atherapeutically effective amount for treating a disease of the posteriorsegment of the eye is an amount sufficient to treat a disease of theposterior segment of the eye.

A therapeutically effective amount of a given API for a given disease tobe treated can be determined based on existing clinical experience usingthe API to treat the disease, or through reasonable amounts ofexperimentation performed in vitro and/or in vivo in animals and/or inhuman subjects.

The therapeutic amount of the API should be selected so as not toprevent formation of a microemulsion. Generally, the API will be presentin an amount less than or equal to about 5 percent (w/v) of thepharmaceutical composition. In various individual embodiments, theamount of API may be selected from 0.01, 0.02, 0.03, 0.04, 0.05, 0.06,0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, and 5.0 percent (w/v).

An aspect of the invention is a method of treating a disease of theposterior segment of the eye. The method includes the step of

topically administering to an eye of a subject in need thereof acomposition comprising an oil-in-water microemulsion comprising

(i) an oil selected from the group consisting of isopropyl myristate,isopropyl palmitate, medium chain triglycerides, and any combinationthereof;

(ii) a pair of surfactants selected from the group consisting of twopolysorbates, a polysorbate and propylene glycol, a polysorbate andglycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane),cremophor EL (polyethoxylated castor oil) and triacetin(1,2,3-triacetoxypropane), and cremophor EL (polyethoxylated castor oil)and propylene glycol;

(iii) water; and

(iv) a therapeutically effective amount, for treating a disease of theposterior segment of the eye, of a lipophilic active pharmaceuticalingredient (API),

wherein:

the API represents about 0.01 to about 5 percent (w/v) of thecomposition;

the water represents 50 to about 95 percent (w/w) of the composition;

the oil and surfactants represent substantially all of the remainder ofthe composition;

the ratio of percent (w/w) total surfactant to percent (w/w) oil is atleast about 10:1;

and

-   -   the composition is formulated for topical administration to the        eye.

As used herein, the terms “treat” or “treating” refer to slowing theprogression of, halting the progression of, reversing the progressionof, or resolving a disease or condition in a subject. In one embodiment,“treat” or “treating” further refer to preventing a disease or conditionin a subject.

As used herein, a “subject” refers to a mammal. In one embodiment, asubject is a human.

The subject can administer the composition to itself, or a caregiver canadminister the composition to the eye of the subject.

In one embodiment, the administering is administering once a day. In oneembodiment, the administering is administering more than once a day. Invarious embodiments, the administering is administering 2 times, 3times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times,11 times, or 12 times a day. In one embodiment, the administering isadministering one time to six times a day.

In one embodiment, the administering involves topically administering asingle drop of the composition to the eye to be treated. Suchsingle-drop administration can include administration 1 time, 2 times, 3times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times,11 times, or 12 times a day.

In one embodiment, the lipophilic API is selected from the groupconsisting of adaprolol maleate, cyclosporine A, fenofibrate, fenofibricacid, indomethacin, miconazole, pilocarpine, piroxicam, and Δ⁸-THC.

In one embodiment, the lipophilic API is fenofibrate

In one embodiment, the lipophilic API is fenofibric acid.

In one embodiment, the lipophilic API is1-acetyl-5-hydroxyanthracene-9,10-dione, represented by

This compound, also known as CLT-005, is disclosed in U.S. Pat. No.8,058,316 to Farjo, the entire content of which is incorporated hereinby reference.

In one embodiment, the disease of the posterior segment of the eye ischaracterized by inflammation, neovascularization, vascular leakage,fibrosis, or any combination thereof.

In one embodiment, the disease of the posterior segment of the eye isselected from the group consisting of: age-related macular degeneration,diabetic retinopathy, posterior uveitis, retinal edema, macular edema,and retinal vein occlusion.

In one embodiment, the disease of the posterior segment of the eye isage-related macular degeneration.

In one embodiment, the disease of the posterior segment of the eye isdry age-related macular degeneration.

In one embodiment, the disease of the posterior segment of the eye iswet age-related macular degeneration.

In one embodiment, the disease of the posterior segment of the eye isdiabetic retinopathy.

An aspect of the invention is a pharmaceutical composition, comprisingan effective amount, for treating a disease of the posterior segment ofthe eye, of a compound represented by

and the pharmaceutical carrier the invention, wherein the pharmaceuticalcomposition is formulated for topical administration to the eye.

In one embodiment, the pharmaceutical composition is formulated aseyedrops.

It will be understood by one of ordinary skill in the relevant arts thatother suitable modifications and adaptations to the compositions andmethods described herein are readily apparent from the description ofthe invention contained herein in view of information known to theordinarily skilled artisan, and may be made without departing from thescope of the invention or any embodiment thereof. Having now describedthe present invention in detail, the same will be more clearlyunderstood by reference to the following examples, which are includedherewith for purposes of illustration only and are not intended to belimiting of the invention.

Examples Example 1 Microemulsion Formulation Library

In order to identify candidate microemulsions useful in accordance withthe invention, over twenty thousand (20,000) formulations representingdifferent combinations of different oils and surfactants were preparedand characterized. Of the tens of thousands of formulations examined,nearly a thousand were identified as candidate microemulsions. Apseudoternary phase diagram was prepared or could be prepared based ondata obtained for each particular combination of oil and surfactants.

As described in Examples 2-4 below, oil-in-water microemulsionformulations comprised of (i) oils selected from isopropyl myristate,isopropyl palmitate, and medium chain triglyceride, and (ii) pairs ofsurfactants selected from Tween® 20, Tween® 80, polypropylene glycol,glycerol, triacetin, and Cremophor® EL were identified.

In addition, each microemulsion was characterized for stability.

In an ongoing effort to characterize the microemulsions, certain of themicroemulsions have been tested for ocular tolerability in mice.

In an ongoing effort to characterize the microemulsions, certain of themicroemulsions have been used in combination with up to 5 percent (w/v)CLT-005.

FIG. 1 presents representative results from part of one singlecombination of oil, surfactants, and water.

FIG. 2 presents a representative pseudoternary phase diagram generatedin accordance with this systematic study. Each filled circle on the plotrepresents a microemulsion. Each unfilled triangle on the plotrepresents a clear mixture that is not a microemulsion, e.g., a liquidcrystal. Each unfilled circle on the plot represents a cloudy mixture.

Example 2 Microemulsion Formulations Comprised of Isopropyl Myristate

Tables 1-26 present representative formulations of microemulsionscomprised of isopropyl myristate and pairs of surfactants selected fromTween® 20 (“T20”), Tween® 80 (“T80”), polypropylene glycol (“P”),glycerol (“G”), triacetin (“TriAc”), and Cremophor® EL (“CEL”).Numerical values are given as percent (w/w). “Surfactant” represents thepercent (w/w) of total surfactant in each formulation.

TABLE 1 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 1 to 1MEM0078 0.473 0.040 0.487 MEM0042 0.498 0.038 0.464 MEM0043 0.523 0.0360.440 MEM0044 0.548 0.035 0.417 MEM0045 0.574 0.033 0.394 MEM0046 0.5990.031 0.370 MEM0047 0.625 0.029 0.346 MEM0048 0.651 0.027 0.322 MEM00790.972 0.002 0.026

TABLE 2 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 2 to 1MEM0080 0.484 0.041 0.475 MEM0056 0.509 0.039 0.452 MEM0057 0.534 0.0370.429 MEM0058 0.559 0.035 0.406 MEM0059 0.584 0.033 0.383

TABLE 3 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 3 to 1MEM0081 0.477 0.041 0.482 MEM0060 0.502 0.039 0.459 MEM0061 0.527 0.0370.436

TABLE 4 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 4 to 1MEM0082 0.475 0.040 0.485 MEM0062 0.500 0.039 0.461 MEM0063 0.525 0.0370.438

TABLE 5 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 5 to 1MEM0083 0.475 0.040 0.484 MEM0064 0.500 0.039 0.461

TABLE 6 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 1 to 2MEM0084 0.485 0.041 0.473 MEM0085 0.510 0.039 0.450 MEM0086 0.535 0.0370.427 MEM0087 0.561 0.035 0.404 MEM0088 0.586 0.033 0.381 MEM0089 0.6110.031 0.358 MEM0090 0.636 0.029 0.334 MEM0091 0.662 0.027 0.311 MEM00920.688 0.025 0.287 MEM0093 0.713 0.023 0.264 MEM0094 0.739 0.021 0.240MEM0095 0.974 0.002 0.024MEM0084-MEM0089 were unstable.

TABLE 7 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 1 to 3MEM0096 0.477 0.041 0.482 MEM0097 0.502 0.039 0.459 MEM0098 0.527 0.0370.436 MEM0099 0.552 0.035 0.413 MEM0049 0.578 0.033 0.390 MEM0027 0.6030.031 0.366 MEM0028 0.629 0.029 0.342 MEM0050 0.654 0.027 0.319 MEM01000.680 0.025 0.295 MEM0101 0.706 0.023 0.271 MEM0051 0.732 0.021 0.247MEM0102 0.758 0.019 0.223 MEM0103 0.785 0.017 0.198 MEM0104 0.811 0.0150.174 MEM0105 0.838 0.013 0.150 MEM0106 0.865 0.010 0.125 MEM0107 0.8910.008 0.100 MEM0108 0.918 0.006 0.075 MEM0109 0.945 0.004 0.050 MEM01100.973 0.002 0.025MEM0096-MEM0099 were unstable.

TABLE 8 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 1 to 4MEM0111 0.478 0.041 0.482 MEM0112 0.503 0.039 0.459 MEM0113 0.528 0.0370.435 MEM0114 0.553 0.035 0.412 MEM0115 0.578 0.033 0.389 MEM0116 0.6110.031 0.358 MEM0117 0.636 0.029 0.334 MEM0052 0.662 0.027 0.311 MEM00530.687 0.025 0.287 MEM0054 0.713 0.023 0.264 MEM0055 0.739 0.021 0.240MEM0118 0.765 0.019 0.217 MEM0119 0.785 0.017 0.198 MEM0120 0.812 0.0150.174 MEM0121 0.838 0.013 0.149 MEM0122 0.865 0.011 0.125 MEM0123 0.8920.008 0.100 MEM0124 0.919 0.006 0.075 MEM0125 0.946 0.004 0.050 MEM01260.973 0.002 0.025MEM0111-MEM0115 were unstable.

TABLE 9 Isopropyl Myristate T20:T80 ID Water Oil Surfactant 1 to 5MEM0127 0.485 0.041 0.473 MEM0128 0.510 0.039 0.450 MEM0129 0.535 0.0370.427 MEM0130 0.561 0.035 0.404 MEM0131 0.586 0.033 0.381 MEM0132 0.6110.031 0.358 MEM0133 0.636 0.029 0.334 MEM0134 0.662 0.027 0.311 MEM01350.688 0.025 0.287 MEM0136 0.713 0.023 0.264 MEM0137 0.739 0.021 0.240MEM0138 0.765 0.019 0.217 MEM0139 0.790 0.017 0.193 MEM0140 0.816 0.0150.169 MEM0141 0.842 0.013 0.145 MEM0142 0.868 0.011 0.121 MEM0143 0.8950.008 0.097 MEM0144 0.921 0.006 0.073 MEM0145 0.947 0.004 0.049 MEM01460.974 0.002 0.024MEM0127-MEM0131 were unstable.

TABLE 10 Isopropyl Myristate T80:P ID Water Oil Surfactant 2 to 1MEM0375 0.492 0.042 0.466 MEM0376 0.517 0.040 0.443 MEM0377 0.542 0.0380.420 MEM0378 0.567 0.036 0.397 MEM0379 0.592 0.034 0.374 MEM0380 0.6180.032 0.351

TABLE 11 Isopropyl Myristate T80:P ID Water Oil Surfactant 3 to 1MEM0381 0.492 0.042 0.466 MEM0382 0.517 0.040 0.443 MEM0383 0.542 0.0380.420 MEM0384 0.567 0.036 0.397 MEM0385 0.592 0.034 0.374 MEM0386 0.6170.031 0.351 MEM0387 0.642 0.029 0.328 MEM0388 0.668 0.027 0.305 MEM03890.693 0.025 0.282 MEM0390 0.744 0.021 0.235 MEM0391 0.769 0.019 0.212MEM0392 0.795 0.017 0.188 MEM0393 0.820 0.015 0.165 MEM0394 0.846 0.0130.142 MEM0395 0.871 0.011 0.118 MEM0396 0.897 0.008 0.095 MEM0397 0.9230.006 0.071 MEM0398 0.948 0.004 0.047 MEM0399 0.974 0.002 0.024

TABLE 12 Isopropyl Myristate T80:P ID Water Oil Surfactant 4 to 1MEM0400 0.567 0.036 0.398 MEM0401 0.592 0.034 0.375 MEM0402 0.617 0.0310.352 MEM0403 0.642 0.029 0.328 MEM0404 0.667 0.027 0.305MEM0400 was unstable.

TABLE 13 Isopropyl Myristate T80:P ID Water Oil Surfactant 5 to 1MEM0405 0.491 0.042 0.467 MEM0406 0.516 0.040 0.444 MEM0407 0.541 0.0380.421 MEM0408 0.566 0.036 0.398 MEM0409 0.592 0.034 0.375 MEM0410 0.6170.031 0.352 MEM0411 0.642 0.029 0.329 MEM0412 0.667 0.027 0.305 MEM04130.693 0.025 0.282 MEM0414 0.718 0.023 0.259 MEM0415 0.743 0.021 0.235MEM0416 0.769 0.019 0.212 MEM0417 0.794 0.017 0.189 MEM0418 0.820 0.0150.165 MEM0419 0.846 0.013 0.142 MEM0420 0.871 0.011 0.118 MEM0421 0.8970.008 0.095 MEM0422 0.923 0.006 0.071 MEM0423 0.948 0.004 0.047 MEM04240.974 0.002 0.024 MEM0425 0.949 0.008 0.042 MEM0426 0.975 0.004 0.021

MEM0405-MEM0408 were unstable.

TABLE 14 Isopropyl Myristate T80:G ID Water Oil Surfactant 1 to 1MEM0578 0.472 0.040 0.488 MEM0579 0.497 0.038 0.465

TABLE 15 Isopropyl Myristate T80:G ID Water Oil Surfactant 3 to 1MEM0033 0.582 0.033 0.385 MEM0580 0.608 0.031 0.361 MEM0581 0.633 0.0290.338 MEM0582 0.659 0.027 0.314 MEM0583 0.684 0.025 0.291

TABLE 16 Isopropyl Myristate T80:G ID Water Oil Surfactant 4 to 1MEM0034 0.483 0.041 0.476 MEM0584 0.508 0.039 0.453 MEM0585 0.533 0.0370.429 MEM0586 0.559 0.035 0.406 MEM0587 0.584 0.033 0.383 MEM0588 0.6090.031 0.360 MEM0589 0.635 0.029 0.336 MEM0590 0.660 0.027 0.313 MEM05910.686 0.025 0.289 MEM0592 0.712 0.023 0.266 MEM0593 0.737 0.021 0.242MEM0594 0.763 0.019 0.218 MEM0595 0.789 0.017 0.194 MEM0596 0.815 0.0150.170 MEM0597 0.841 0.013 0.146 MEM0598 0.868 0.011 0.122 MEM0599 0.8940.008 0.098 MEM0600 0.920 0.006 0.073 MEM0601 0.947 0.004 0.049 MEM06020.973 0.002 0.025

TABLE 17 Isopropyl Myristate T80:G ID Water Oil Surfactant 5 to 1MEM0603 0.485 0.041 0.474 MEM0604 0.510 0.039 0.451 MEM0605 0.535 0.0370.428 MEM0606 0.560 0.035 0.405 MEM0607 0.585 0.033 0.382 MEM0608 0.6100.031 0.358 MEM0609 0.636 0.029 0.335 MEM0610 0.661 0.027 0.312 MEM06110.687 0.025 0.288 MEM0612 0.712 0.023 0.265 MEM0613 0.738 0.021 0.241MEM0614 0.764 0.019 0.217 MEM0615 0.790 0.017 0.193 MEM0616 0.816 0.0150.169 MEM0617 0.842 0.013 0.145 MEM0618 0.868 0.011 0.121 MEM0619 0.8940.008 0.097 MEM0620 0.921 0.006 0.073 MEM0621 0.947 0.004 0.049 MEM06220.973 0.002 0.024

TABLE 18 Isopropyl Myristate T80:TriAc ID Water Oil Surfactant 1 to 1MEM0872 0.840 0.013 0.148 MEM0873 0.866 0.011 0.123

TABLE 19 Isopropyl Myristate T80:TriAc ID Water Oil Surfactant 2 to 1MEM0874 0.661 0.027 0.312 MEM0875 0.712 0.023 0.265 MEM0876 0.738 0.0210.242 MEM0877 0.763 0.019 0.218 MEM0878 0.789 0.017 0.194 MEM0879 0.8150.015 0.170 MEM0880 0.842 0.013 0.146 MEM0881 0.868 0.011 0.122 MEM08820.894 0.008 0.098 MEM0883 0.920 0.006 0.073 MEM0884 0.947 0.004 0.049MEM0885 0.973 0.002 0.025

TABLE 20 Isopropyl Myristate T80:TriAc ID Water Oil Surfactant 3 to 1MEM0886 0.485 0.041 0.473 MEM0023 0.510 0.039 0.450 MEM0887 0.536 0.0370.427 MEM0888 0.561 0.035 0.404 MEM0889 0.586 0.033 0.381 MEM0890 0.6110.031 0.358 MEM0891 0.637 0.029 0.334 MEM0892 0.662 0.027 0.311 MEM08930.688 0.025 0.287 MEM0894 0.713 0.023 0.264 MEM0895 0.739 0.021 0.240MEM0896 0.765 0.019 0.216 MEM0897 0.791 0.017 0.193 MEM0898 0.816 0.0150.169 MEM0899 0.842 0.013 0.145 MEM0900 0.868 0.011 0.121 MEM0901 0.8950.008 0.097 MEM0902 0.921 0.006 0.073 MEM0903 0.947 0.004 0.049 MEM09040.974 0.002 0.024 MEM0905 0.491 0.083 0.426 MEM0024 0.516 0.079 0.405MEM0906 0.541 0.075 0.384

TABLE 21 Isopropyl Myristate T80:TriAc ID Water Oil Surfactant 4 to 1MEM0907 0.486 0.041 0.472 MEM0908 0.511 0.039 0.449 MEM0909 0.537 0.0370.426 MEM0910 0.562 0.035 0.403 MEM0911 0.587 0.033 0.380 MEM0912 0.6120.031 0.357 MEM0913 0.638 0.029 0.333 MEM0914 0.663 0.027 0.310 MEM09150.688 0.025 0.286 MEM0916 0.714 0.023 0.263 MEM0917 0.740 0.021 0.239MEM0918 0.765 0.019 0.216 MEM0919 0.791 0.017 0.192 MEM0920 0.817 0.0150.168 MEM0921 0.843 0.013 0.144 MEM0922 0.869 0.011 0.121 MEM0923 0.8950.008 0.097 MEM0924 0.921 0.006 0.073 MEM0925 0.947 0.004 0.048 MEM09260.974 0.002 0.024

TABLE 22 Isopropyl Myristate T80:TriAc ID Water Oil Surfactant 5 to 1MEM0927 0.487 0.041 0.471 MEM0928 0.512 0.039 0.448 MEM0929 0.537 0.0370.425 MEM0930 0.562 0.035 0.402 MEM0931 0.588 0.033 0.379 MEM0932 0.6130.031 0.356 MEM0933 0.638 0.029 0.333 MEM0934 0.664 0.027 0.309 MEM09350.689 0.025 0.286 MEM0936 0.715 0.023 0.262 MEM0937 0.740 0.021 0.239MEM0938 0.766 0.019 0.215 MEM0939 0.792 0.017 0.192 MEM0940 0.817 0.0150.168 MEM0941 0.843 0.013 0.144 MEM0942 0.869 0.011 0.120 MEM0943 0.8950.008 0.096 MEM0944 0.921 0.006 0.072 MEM0945 0.947 0.004 0.048 MEM09460.974 0.002 0.024

TABLE 23 Isopropyl Myristate CEL:TriAc ID Water Oil Surfactant 3 to 1MEM1009 0.588 0.033 0.379 MEM1010 0.613 0.031 0.356 MEM1011 0.638 0.0290.333 MEM1012 0.664 0.027 0.309 MEM1013 0.689 0.025 0.286 MEM1014 0.7150.023 0.262 MEM1015 0.740 0.021 0.239 MEM1016 0.766 0.019 0.215 MEM10170.792 0.017 0.192 MEM1018 0.817 0.015 0.168 MEM1019 0.843 0.013 0.144MEM1020 0.869 0.011 0.120 MEM1021 0.895 0.008 0.096 MEM1022 0.921 0.0060.072 MEM1023 0.947 0.004 0.048 MEM1024 0.974 0.002 0.024 MEM0032 0.6180.063 0.319 MEM1025 0.643 0.059 0.298 MEM1026 0.668 0.055 0.277 MEM10270.694 0.051 0.256 MEM1028 0.719 0.046 0.235 MEM1029 0.744 0.042 0.213MEM1030 0.770 0.038 0.192 MEM1031 0.795 0.034 0.171 MEM1032 0.821 0.0300.150 MEM1033 0.846 0.025 0.128 MEM1034 0.872 0.021 0.107 MEM1035 0.8970.017 0.086 MEM1036 0.923 0.013 0.064 MEM1037 0.949 0.008 0.043 MEM10380.974 0.004 0.021

TABLE 24 Isopropyl Myristate CEL:P ID Water Oil Surfactant 2 to 1MEM0022 0.081 0.077 0.842 MEM1039 0.494 0.042 0.464 MEM0016 0.503 0.0390.458 MEM1040 0.519 0.040 0.441 MEM1041 0.544 0.038 0.418 MEM1042 0.5690.036 0.395 MEM1043 0.594 0.034 0.372 MEM1044 0.619 0.032 0.349 MEM10450.644 0.029 0.326 MEM1046 0.669 0.027 0.303 MEM1047 0.695 0.025 0.280MEM1048 0.720 0.023 0.257 MEM1049 0.745 0.021 0.234 MEM0010 0.771 0.0190.210 MEM1050 0.796 0.017 0.187 MEM1051 0.821 0.015 0.164 MEM1052 0.8470.013 0.141 MEM1053 0.872 0.011 0.117 MEM1054 0.898 0.008 0.094 MEM10550.923 0.006 0.070 MEM1056 0.949 0.004 0.047 MEM1057 0.974 0.002 0.024

TABLE 25 Isopropyl Myristate CEL:P ID Water Oil Surfactant 3 to 1MEM1058 0.669 0.027 0.303 MEM1059 0.694 0.025 0.280 MEM1060 0.720 0.0230.257 MEM1061 0.745 0.021 0.234 MEM1062 0.770 0.019 0.211 MEM1063 0.7960.017 0.187 MEM1064 0.821 0.015 0.164 MEM1065 0.847 0.013 0.141 MEM10660.872 0.011 0.117 MEM1067 0.898 0.008 0.094 MEM1068 0.923 0.006 0.070MEM1069 0.949 0.004 0.047 MEM1070 0.974 0.002 0.024

TABLE 26 Isopropyl Myristate CEL:P ID Water Oil Surfactant 4 to 1MEM1071 0.669 0.027 0.304 MEM1072 0.694 0.025 0.280 MEM1073 0.720 0.0230.257 MEM1074 0.745 0.021 0.234 MEM1075 0.770 0.019 0.211 MEM1076 0.7960.017 0.187 MEM1077 0.821 0.015 0.164 MEM1078 0.847 0.013 0.141 MEM10790.872 0.011 0.117 MEM1080 0.898 0.008 0.094 MEM1081 0.923 0.006 0.071MEM1082 0.949 0.004 0.047 MEM1083 0.974 0.002 0.024 MEM1084 0.548 0.0760.376 MEM1085 0.573 0.072 0.355 MEM0031 0.598 0.068 0.334 MEM1086 0.6230.064 0.313 MEM1087 0.648 0.059 0.292 MEM1088 0.673 0.055 0.272 MEM10890.698 0.051 0.251 MEM1090 0.723 0.047 0.230 MEM1091 0.749 0.042 0.209MEM1092 0.774 0.038 0.188 MEM1093 0.799 0.034 0.167 MEM1094 0.824 0.0300.146 MEM1095 0.849 0.025 0.126 MEM1096 0.874 0.021 0.105 MEM1097 0.8990.017 0.084 MEM1098 0.924 0.013 0.063 MEM1099 0.950 0.008 0.042 MEM11000.975 0.004 0.021

Example 3 Microemulsion Formulations Comprised of Isopropyl Palmitate

Tables 27-45 present representative formulations of microemulsionscomprised of isopropyl palmitate and pairs of surfactants selected fromTween® 20 (“T20”), Tween® 80 (“T80”), polypropylene glycol (“P”), andglycerol (“G”). Numerical values are given as percent (w/w).“Surfactant” represents the percent (w/w) of total surfactant in eachformulation.

TABLE 27 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 1 to 1MEM0147 0.486 0.041 0.472 MEM0148 0.511 0.039 0.449 MEM0149 0.536 0.0370.426 MEM0150 0.561 0.035 0.403 MEM0151 0.587 0.033 0.380 MEM0152 0.6120.031 0.357MEM0147-MEM0152 were unstable.

TABLE 28 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 2 to 1MEM0153 0.485 0.041 0.474 MEM0154 0.510 0.039 0.451MEM0153 and MEM0154 were unstable.

TABLE 29 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 3 to 1MEM0155 0.484 0.041 0.475 MEM0156 0.509 0.039 0.452 MEM0157 0.534 0.0370.429 MEM0030 0.559 0.035 0.406 MEM0158 0.585 0.033 0.382 MEM0159 0.6100.031 0.359

TABLE 30 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 4 to 1MEM0160 0.484 0.041 0.475 MEM0161 0.509 0.039 0.452 MEM0162 0.534 0.0370.429 MEM0163 0.559 0.035 0.406 MEM0164 0.584 0.033 0.383 MEM0165 0.9780.019 0.003

TABLE 31 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 5 to 1MEM0166 0.483 0.041 0.475 MEM0167 0.508 0.039 0.452 MEM0168 0.978 0.0190.003 MEM0169 0.973 0.002 0.025

TABLE 32 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 1 to 2MEM0170 0.488 0.042 0.471 MEM0171 0.513 0.040 0.448 MEM0172 0.538 0.0380.425 MEM0173 0.563 0.035 0.402 MEM0174 0.588 0.033 0.379 MEM0175 0.6130.031 0.355 MEM0176 0.639 0.029 0.332 MEM0177 0.664 0.027 0.309 MEM01780.689 0.025 0.285 MEM0179 0.948 0.004 0.048 MEM0180 0.974 0.002 0.024MEM0170-MEM0175 were unstable.

TABLE 33 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 1 to 3MEM0181 0.488 0.042 0.470 MEM0182 0.513 0.040 0.447 MEM0183 0.538 0.0380.424 MEM0184 0.563 0.036 0.401 MEM0185 0.589 0.033 0.378 MEM0186 0.6140.031 0.355 MEM0187 0.639 0.029 0.331 MEM0188 0.665 0.027 0.308 MEM01890.690 0.025 0.285 MEM0190 0.716 0.023 0.261 MEM0191 0.741 0.021 0.238MEM0192 0.767 0.019 0.214 MEM0193 0.792 0.017 0.191 MEM0194 0.818 0.0150.167 MEM0195 0.844 0.013 0.143 MEM0196 0.870 0.011 0.120 MEM0197 0.8960.008 0.096 MEM0198 0.922 0.006 0.072 MEM0199 0.948 0.004 0.048 MEM02000.974 0.002 0.024 MEM0201 0.974 0.004 0.021MEM0181-MEM0187 were unstable.

TABLE 34 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 1 to 4MEM0202 0.489 0.042 0.470 MEM0203 0.514 0.040 0.447 MEM0204 0.539 0.0380.424 MEM0205 0.564 0.036 0.401 MEM0206 0.589 0.033 0.377 MEM0207 0.6140.031 0.354 MEM0208 0.640 0.029 0.331 MEM0209 0.665 0.027 0.308 MEM02100.690 0.025 0.284 MEM0211 0.716 0.023 0.261 MEM0212 0.741 0.021 0.238MEM0213 0.767 0.019 0.214 MEM0214 0.793 0.017 0.190 MEM0215 0.818 0.0150.167 MEM0216 0.844 0.013 0.143 MEM0217 0.870 0.011 0.119 MEM0218 0.8960.008 0.096 MEM0219 0.922 0.006 0.072 MEM0220 0.948 0.004 0.048 MEM02210.974 0.002 0.024 MEM0222 0.974 0.004 0.021MEM0202-MEM0208 were unstable.

TABLE 35 Isopropyl Palmitate T20:T80 ID Water Oil Surfactant 1 to 5MEM0223 0.489 0.042 0.469 MEM0224 0.514 0.040 0.446 MEM0225 0.539 0.0380.423 MEM0226 0.564 0.036 0.400 MEM0227 0.589 0.034 0.377 MEM0228 0.6150.031 0.354 MEM0229 0.640 0.029 0.331 MEM0230 0.665 0.027 0.307 MEM02310.691 0.025 0.284 MEM0232 0.716 0.023 0.261 MEM0233 0.742 0.021 0.237MEM0234 0.767 0.019 0.214 MEM0235 0.793 0.017 0.190 MEM0236 0.819 0.0150.167 MEM0237 0.844 0.013 0.143 MEM0238 0.870 0.011 0.119 MEM0239 0.8960.008 0.096 MEM0240 0.922 0.006 0.072 MEM0241 0.948 0.004 0.048 MEM02420.974 0.002 0.024 MEM0243 0.974 0.004 0.021MEM0223-MEM0230 were unstable.

TABLE 36 Isopropyl Palmitate T80:P ID Water Oil Surfactant 1 to 1MEM0427 0.846 0.013 0.141 MEM0428 0.872 0.011 0.117 MEM0429 0.897 0.0090.094 MEM0430 0.923 0.006 0.071 MEM0431 0.949 0.004 0.047 MEM0432 0.9740.002 0.024

TABLE 37 Isopropyl Palmitate T80:P ID Water Oil Surfactant 2 to 1MEM0433 0.492 0.042 0.466 MEM0434 0.542 0.038 0.420 MEM0435 0.592 0.0340.374 MEM0436 0.948 0.004 0.047 MEM0437 0.974 0.002 0.024 MEM0438 0.9750.004 0.021

TABLE 38 Isopropyl Palmitate T80:P ID Water Oil Surfactant 3 to 1MEM0439 0.492 0.042 0.466 MEM0440 0.517 0.040 0.443 MEM0441 0.542 0.0380.420 MEM0442 0.567 0.036 0.397 MEM0443 0.592 0.034 0.374 MEM0444 0.6170.032 0.351 MEM0445 0.642 0.029 0.328 MEM0446 0.693 0.025 0.282 MEM04470.795 0.017 0.188 MEM0448 0.846 0.013 0.142 MEM0449 0.871 0.011 0.118MEM0450 0.897 0.008 0.095 MEM0451 0.923 0.006 0.071 MEM0452 0.948 0.0040.047 MEM0453 0.974 0.002 0.024 MEM0454 0.924 0.013 0.063 MEM0455 0.9490.009 0.042 MEM0456 0.975 0.004 0.021

TABLE 39 Isopropyl Palmitate T80:P ID Water Oil Surfactant 4 to 1MEM0041 0.491 0.042 0.467 MEM0457 0.516 0.040 0.444 MEM0458 0.542 0.0380.421 MEM0459 0.567 0.036 0.398 MEM0460 0.592 0.034 0.375 MEM0461 0.6170.032 0.352 MEM0462 0.642 0.029 0.328 MEM0463 0.820 0.015 0.165 MEM04640.846 0.013 0.142 MEM0465 0.871 0.011 0.118 MEM0466 0.897 0.008 0.095MEM0467 0.923 0.006 0.071 MEM0468 0.948 0.004 0.047 MEM0469 0.974 0.0020.024

TABLE 40 Isopropyl Palmitate T80:P ID Water Oil Surfactant 5 to 1MEM0470 0.491 0.042 0.467 MEM0471 0.516 0.040 0.444 MEM0472 0.541 0.0380.421 MEM0473 0.566 0.036 0.398 MEM0474 0.592 0.034 0.375 MEM0475 0.6170.032 0.352 MEM0476 0.642 0.029 0.329 MEM0477 0.667 0.027 0.305 MEM04780.693 0.025 0.282 MEM0479 0.718 0.023 0.259 MEM0480 0.743 0.021 0.235MEM0481 0.769 0.019 0.212 MEM0482 0.794 0.017 0.189 MEM0483 0.820 0.0150.165 MEM0484 0.845 0.013 0.142 MEM0485 0.871 0.011 0.118 MEM0486 0.8970.008 0.095 MEM0487 0.923 0.006 0.071 MEM0488 0.948 0.004 0.047 MEM04890.974 0.002 0.024 MEM0490 0.848 0.026 0.126 MEM0491 0.873 0.021 0.105MEM0492 0.899 0.017 0.084 MEM0493 0.924 0.013 0.063 MEM0494 0.949 0.0090.042 MEM0495 0.975 0.004 0.021 MEM0496 0.900 0.026 0.074 MEM0497 0.9250.019 0.055 MEM0498 0.950 0.013 0.037 MEM0499 0.975 0.006 0.018MEM0470-MEM0473 were unstable.

TABLE 41 Isopropyl Palmitate T80:G ID Water Oil Surfactant 1 to 1MEM0623 0.472 0.040 0.488 MEM0035 0.497 0.038 0.464 MEM0624 0.522 0.0360.441 MEM0625 0.944 0.004 0.051 MEM0626 0.972 0.002 0.026

TABLE 42 Isopropyl Palmitate T80:G ID Water Oil Surfactant 2 to 1MEM0036 0.478 0.041 0.481 MEM0037 0.503 0.039 0.458 MEM0627 0.529 0.0370.435 MEM0628 0.554 0.035 0.411 MEM0629 0.579 0.033 0.388 MEM0630 0.6050.031 0.365 MEM0631 0.630 0.029 0.341 MEM0632 0.656 0.027 0.317 MEM06330.733 0.021 0.246 MEM0634 0.760 0.019 0.222 MEM0635 0.786 0.017 0.197

TABLE 43 Isopropyl Palmitate T80:G ID Water Oil Surfactant 3 to 1MEM0038 0.481 0.041 0.477 MEM0636 0.506 0.039 0.454 MEM0637 0.532 0.0370.431 MEM0638 0.557 0.035 0.408 MEM0639 0.582 0.033 0.385 MEM0640 0.6070.031 0.361 MEM0641 0.633 0.029 0.338 MEM0642 0.659 0.027 0.314 MEM06430.684 0.025 0.291 MEM0644 0.736 0.021 0.243 MEM0645 0.762 0.019 0.219MEM0646 0.788 0.017 0.195 MEM0647 0.814 0.015 0.171 MEM0648 0.840 0.0130.147 MEM0649 0.867 0.011 0.123 MEM0650 0.893 0.008 0.098 MEM0651 0.9200.006 0.074 MEM0652 0.895 0.017 0.088 MEM0653 0.921 0.013 0.066 MEM06540.948 0.009 0.044 MEM0655 0.974 0.004 0.022

TABLE 44 Isopropyl Palmitate T80:G ID Water Oil Surfactant 4 to 1MEM0656 0.483 0.041 0.476 MEM0657 0.508 0.039 0.452 MEM0658 0.533 0.0370.429 MEM0659 0.559 0.035 0.406 MEM0660 0.584 0.033 0.383 MEM0661 0.6090.031 0.360 MEM0662 0.635 0.029 0.336 MEM0663 0.660 0.027 0.313 MEM06640.686 0.025 0.289 MEM0665 0.711 0.023 0.266 MEM0666 0.737 0.021 0.242MEM0667 0.763 0.019 0.218 MEM0668 0.789 0.017 0.194 MEM0669 0.815 0.0150.170 MEM0670 0.841 0.013 0.146 MEM0671 0.868 0.011 0.122 MEM0672 0.8940.008 0.098 MEM0673 0.920 0.006 0.073 MEM0674 0.947 0.004 0.049 MEM06750.973 0.002 0.025 MEM0676 0.665 0.055 0.280 MEM0677 0.691 0.050 0.259MEM0678 0.716 0.046 0.238 MEM0679 0.742 0.042 0.216 MEM0680 0.767 0.0380.195 MEM0681 0.793 0.034 0.173 MEM0682 0.819 0.030 0.152 MEM0683 0.8440.025 0.130 MEM0684 0.870 0.021 0.109 MEM0685 0.896 0.017 0.087 MEM06860.922 0.013 0.065 MEM0687 0.948 0.009 0.044 MEM0688 0.974 0.004 0.022

TABLE 45 Isopropyl Palmitate T80:G ID Water Oil Surfactant 5 to 1MEM0689 0.484 0.041 0.474 MEM0690 0.509 0.039 0.451 MEM0691 0.535 0.0370.428 MEM0692 0.560 0.035 0.405 MEM0693 0.585 0.033 0.382 MEM0694 0.6100.031 0.358 MEM0695 0.636 0.029 0.335 MEM0696 0.661 0.027 0.312 MEM06970.687 0.025 0.288 MEM0698 0.712 0.023 0.265 MEM0699 0.738 0.021 0.241MEM0700 0.764 0.019 0.217 MEM0701 0.790 0.017 0.193 MEM0702 0.816 0.0150.169 MEM0703 0.842 0.013 0.145 MEM0704 0.868 0.011 0.121 MEM0705 0.8940.008 0.097 MEM0706 0.921 0.006 0.073 MEM0707 0.947 0.004 0.049 MEM07080.973 0.002 0.024 MEM0709 0.666 0.055 0.279 MEM0710 0.692 0.051 0.258MEM0711 0.717 0.046 0.237 MEM0712 0.742 0.042 0.215 MEM0713 0.768 0.0380.194 MEM0714 0.794 0.034 0.173 MEM0715 0.819 0.030 0.151 MEM0716 0.8450.025 0.130 MEM0717 0.871 0.021 0.108 MEM0718 0.896 0.017 0.087 MEM07190.922 0.013 0.065 MEM0720 0.948 0.009 0.043 MEM0721 0.974 0.004 0.022

Example 4 Microemulsion Formulations Comprised of Medium ChainTriglyceride

Tables 46-68 present representative formulations of microemulsionscomprised of medium chain triglyceride (“MCT”) and pairs of surfactantsselected from Tween® 20 (“T20”), Tween® 80 (“T80”), polypropylene glycol(“P”), glycerol (“G”), triacetin (“TriAc”), and Cremophor® EL (“CEL”).Numerical values are given as percent (w/w). “Surfactant” represents thepercent (w/w) of total surfactant in each formulation.

TABLE 46 MCT T20:T80 ID Water Oil Surfactant 1 to 1 MEM0244 0.484 0.0460.470 MEM0245 0.509 0.044 0.448 MEM0246 0.534 0.041 0.425 MEM0065 0.5590.039 0.402 MEM0247 0.584 0.037 0.379 MEM0248 0.610 0.035 0.356 MEM00660.635 0.032 0.332 MEM0249 0.661 0.030 0.309 MEM0067 0.686 0.028 0.286MEM0250 0.712 0.026 0.262 MEM0251 0.738 0.023 0.239 MEM0252 0.764 0.0210.215 MEM0253 0.789 0.019 0.192 MEM0254 0.816 0.016 0.168 MEM0255 0.8420.014 0.144 MEM0256 0.920 0.007 0.073 MEM0257 0.973 0.002 0.024 MEM02580.976 0.021 0.003

TABLE 47 MCT T20:T80 ID Water Oil Surfactant 2 to 1 MEM0259 0.483 0.0460.472 MEM0260 0.508 0.043 0.449 MEM0261 0.973 0.002 0.024 MEM0262 0.9280.064 0.008 MEM0263 0.952 0.043 0.005 MEM0264 0.976 0.021 0.003MEM0259 and MEM0260 were unstable.

TABLE 48 MCT T20:T80 ID Water Oil Surfactant 3 to 1 MEM0265 0.482 0.0460.473 MEM0266 0.507 0.043 0.450 MEM0267 0.532 0.041 0.427 MEM0268 0.5570.039 0.404 MEM0269 0.582 0.037 0.381 MEM0270 0.608 0.034 0.358 MEM02710.928 0.064 0.008 MEM0272 0.952 0.043 0.005 MEM0273 0.976 0.021 0.003

TABLE 49 MCT T20:T80 ID Water Oil Surfactant 4 to 1 MEM0274 0.946 0.0050.049 MEM0275 0.973 0.002 0.025 MEM0276 0.904 0.085 0.010 MEM0277 0.9280.064 0.008 MEM0278 0.952 0.043 0.005 MEM0279 0.976 0.021 0.003

TABLE 50 MCT T20:T80 ID Water Oil Surfactant 5 to 1 MEM0280 0.974 0.0070.019 MEM0281 0.948 0.019 0.033 MEM0282 0.974 0.009 0.016 MEM0283 0.9280.064 0.008 MEM0284 0.952 0.043 0.005 MEM0285 0.976 0.021 0.003

TABLE 51 MCT T20:T80 ID Water Oil Surfactant 1 to 2 MEM0286 0.485 0.0460.469 MEM0287 0.510 0.044 0.446 MEM0288 0.535 0.041 0.423 MEM0289 0.5610.039 0.400 MEM0290 0.586 0.037 0.377 MEM0291 0.611 0.035 0.354 MEM02920.637 0.032 0.331 MEM0293 0.662 0.030 0.308 MEM0068 0.688 0.028 0.285MEM0069 0.713 0.026 0.261 MEM0294 0.739 0.023 0.238 MEM0295 0.765 0.0210.214 MEM0296 0.790 0.019 0.191 MEM0297 0.816 0.016 0.167 MEM0298 0.8420.014 0.144 MEM0299 0.868 0.012 0.120 MEM0300 0.895 0.009 0.096 MEM03010.921 0.007 0.072 MEM0302 0.947 0.005 0.048 MEM0303 0.974 0.002 0.024MEM0286-MEM0292 were unstable.

TABLE 52 MCT T20:T80 ID Water Oil Surfactant 1 to 3 MEM0304 0.486 0.0460.468 MEM0305 0.511 0.044 0.445 MEM0070 0.536 0.041 0.422 MEM0306 0.5610.039 0.400 MEM0071 0.587 0.037 0.377 MEM0072 0.612 0.035 0.354 MEM03070.637 0.032 0.330 MEM0308 0.663 0.030 0.307 MEM0309 0.688 0.028 0.284MEM0310 0.714 0.026 0.261 MEM0311 0.739 0.023 0.237 MEM0312 0.765 0.0210.214 MEM0313 0.791 0.019 0.190 MEM0314 0.817 0.016 0.167 MEM0315 0.8430.014 0.143 MEM0316 0.869 0.012 0.120 MEM0317 0.895 0.009 0.096 MEM03180.921 0.007 0.072 MEM0319 0.947 0.005 0.048 MEM0320 0.974 0.002 0.024MEM0321 0.793 0.037 0.170 MEM0322 0.819 0.033 0.149 MEM0323 0.844 0.0280.128 MEM0324 0.974 0.005 0.021MEM0304 and MEM0305 were unstable.

TABLE 53 MCT T20:T80 ID Water Oil Surfactant 1 to 4 MEM0325 0.486 0.0460.468 MEM0326 0.511 0.044 0.445 MEM0327 0.537 0.041 0.422 MEM0328 0.5620.039 0.399 MEM0329 0.587 0.037 0.376 MEM0073 0.612 0.035 0.353 MEM00740.638 0.032 0.330 MEM0075 0.663 0.030 0.307 MEM0076 0.688 0.028 0.284MEM0330 0.714 0.026 0.260 MEM0331 0.740 0.023 0.237 MEM0332 0.765 0.0210.214 MEM0333 0.791 0.019 0.190 MEM0334 0.817 0.016 0.167 MEM0335 0.8430.014 0.143 MEM0336 0.869 0.012 0.119 MEM0337 0.895 0.009 0.096 MEM03380.921 0.007 0.072 MEM0339 0.947 0.005 0.048 MEM0340 0.974 0.002 0.024MEM0341 0.793 0.037 0.169 MEM0342 0.819 0.033 0.148 MEM0343 0.845 0.0280.127 MEM0344 0.948 0.009 0.043 MEM0345 0.974 0.005 0.021MEM0325-MEM0327 were unstable.

TABLE 54 MCT T20:T80 ID Water Oil Surfactant 1 to 5 MEM0346 0.487 0.0460.467 MEM0347 0.512 0.044 0.444 MEM0348 0.537 0.042 0.422 MEM0349 0.5620.039 0.399 MEM0350 0.587 0.037 0.376 MEM0351 0.613 0.035 0.353 MEM03520.638 0.032 0.330 MEM0077 0.663 0.030 0.306 MEM0353 0.689 0.028 0.283MEM0354 0.714 0.026 0.260 MEM0355 0.740 0.023 0.237 MEM0356 0.766 0.0210.213 MEM0357 0.791 0.019 0.190 MEM0358 0.817 0.016 0.166 MEM0359 0.8430.014 0.143 MEM0360 0.869 0.012 0.119 MEM0361 0.895 0.009 0.095 MEM03620.921 0.007 0.072 MEM0363 0.947 0.005 0.048 MEM0364 0.974 0.002 0.024MEM0365 0.641 0.065 0.294 MEM0366 0.666 0.061 0.273 MEM0367 0.691 0.0560.253 MEM0368 0.717 0.051 0.232 MEM0369 0.742 0.047 0.211 MEM0370 0.7680.042 0.190 MEM0371 0.793 0.037 0.169 MEM0372 0.819 0.033 0.148 MEM03730.845 0.028 0.127 MEM0374 0.948 0.009 0.043MEM0346-MEM0352 were unstable.

TABLE 55 MCT T80:P ID Water Oil Surfactant 2 to 1 MEM0500 0.540 0.0420.418 MEM0501 0.590 0.037 0.373 MEM0502 0.641 0.033 0.327 MEM0503 0.7930.019 0.188 MEM0504 0.819 0.016 0.164 MEM0505 0.845 0.014 0.141 MEM05060.871 0.012 0.118 MEM0507 0.896 0.009 0.094 MEM0508 0.922 0.007 0.071MEM0509 0.948 0.005 0.047 MEM0510 0.974 0.002 0.024

TABLE 56 MCT T80:P ID Water Oil Surfactant 3 to 1 MEM0511 0.489 0.0460.464 MEM0512 0.514 0.044 0.442 MEM0513 0.540 0.042 0.419 MEM0514 0.5650.039 0.396 MEM0515 0.590 0.037 0.373 MEM0516 0.615 0.035 0.350 MEM05170.640 0.033 0.327 MEM0518 0.666 0.030 0.304 MEM0519 0.691 0.028 0.281MEM0520 0.717 0.026 0.258 MEM0521 0.742 0.023 0.235 MEM0522 0.768 0.0210.211 MEM0523 0.793 0.019 0.188 MEM0524 0.819 0.016 0.165 MEM0525 0.8450.014 0.141 MEM0526 0.870 0.012 0.118 MEM0527 0.896 0.009 0.094 MEM05280.922 0.007 0.071 MEM0529 0.948 0.005 0.047 MEM0530 0.974 0.002 0.024

TABLE 57 MCT T80:P ID Water Oil Surfactant 4 to 1 MEM0531 0.489 0.0460.465 MEM0532 0.514 0.044 0.442 MEM0533 0.539 0.042 0.419 MEM0534 0.5640.039 0.396 MEM0535 0.590 0.037 0.373 MEM0536 0.615 0.035 0.350 MEM05370.640 0.033 0.327 MEM0538 0.691 0.028 0.281 MEM0539 0.716 0.026 0.258MEM0540 0.742 0.023 0.235 MEM0541 0.767 0.021 0.212 MEM0542 0.793 0.0190.188 MEM0543 0.819 0.016 0.165 MEM0544 0.844 0.014 0.142 MEM0545 0.8700.012 0.118 MEM0546 0.896 0.009 0.095 MEM0547 0.922 0.007 0.071 MEM05480.948 0.005 0.047 MEM0549 0.974 0.002 0.024

TABLE 58 MCT T80:P ID Water Oil Surfactant 5 to 1 MEM0550 0.489 0.0460.465 MEM0551 0.514 0.044 0.442 MEM0552 0.539 0.042 0.419 MEM0020 0.5640.039 0.396 MEM0553 0.589 0.037 0.373 MEM0554 0.615 0.035 0.350 MEM05550.640 0.033 0.327 MEM0556 0.665 0.030 0.304 MEM0557 0.691 0.028 0.281MEM0558 0.716 0.026 0.258 MEM0559 0.742 0.023 0.235 MEM0560 0.767 0.0210.212 MEM0561 0.793 0.019 0.188 MEM0562 0.819 0.016 0.165 MEM0563 0.8440.014 0.142 MEM0564 0.870 0.012 0.118 MEM0565 0.896 0.009 0.095 MEM05660.922 0.007 0.071 MEM0567 0.948 0.005 0.047 MEM0568 0.974 0.002 0.024MEM0008 0.592 0.075 0.333 MEM0569 0.642 0.065 0.292 MEM0570 0.795 0.0380.168 MEM0571 0.820 0.033 0.147 MEM0572 0.846 0.028 0.126 MEM0573 0.8710.024 0.105 MEM0574 0.897 0.019 0.084 MEM0575 0.923 0.014 0.063 MEM05760.948 0.009 0.042 MEM0577 0.974 0.005 0.021

TABLE 59 MCT T80:G ID Water Oil Surfactant 1 to 1 MEM0722 0.495 0.0420.463 MEM0723 0.520 0.040 0.440 MEM0724 0.546 0.038 0.416 MEM0019 0.5710.036 0.393 MEM0725 0.597 0.034 0.370 MEM0726 0.622 0.032 0.346 MEM07270.648 0.029 0.322 MEM0728 0.674 0.027 0.298 MEM0729 0.701 0.025 0.274MEM0730 0.727 0.023 0.250 MEM0731 0.753 0.021 0.226 MEM0732 0.780 0.0180.201 MEM0733 0.807 0.016 0.177 MEM0734 0.834 0.014 0.152 MEM0735 0.8610.012 0.127 MEM0736 0.889 0.009 0.102 MEM0737 0.916 0.007 0.077 MEM07380.944 0.005 0.051 MEM0739 0.972 0.002 0.026

TABLE 60 MCT T80:G ID Water Oil Surfactant 2 to 1 MEM0740 0.476 0.0450.479 MEM0741 0.501 0.043 0.456 MEM0742 0.526 0.041 0.433 MEM0743 0.5520.039 0.410 MEM0744 0.577 0.036 0.387 MEM0745 0.603 0.034 0.363 MEM07460.628 0.032 0.340 MEM0747 0.654 0.030 0.316 MEM0748 0.680 0.028 0.293MEM0749 0.706 0.025 0.269 MEM0750 0.732 0.023 0.245 MEM0751 0.758 0.0210.221 MEM0752 0.784 0.019 0.197 MEM0753 0.811 0.016 0.173 MEM0754 0.8380.014 0.149 MEM0755 0.864 0.012 0.124 MEM0756 0.891 0.009 0.100 MEM07570.918 0.007 0.075 MEM0758 0.945 0.005 0.050 MEM0759 0.973 0.002 0.025MEM0760 0.866 0.023 0.111 MEM0761 0.893 0.019 0.089 MEM0762 0.919 0.0140.067 MEM0763 0.946 0.009 0.044 MEM0764 0.973 0.005 0.022

TABLE 61 MCT T80:G ID Water Oil Surfactant 3 to 1 MEM0765 0.479 0.0450.475 MEM0766 0.504 0.043 0.453 MEM0767 0.529 0.041 0.430 MEM0768 0.5550.039 0.407 MEM0769 0.580 0.037 0.383 MEM0770 0.605 0.034 0.360 MEM07710.631 0.032 0.337 MEM0772 0.657 0.030 0.314 MEM0773 0.682 0.028 0.290MEM0774 0.708 0.025 0.266 MEM0775 0.734 0.023 0.243 MEM0776 0.760 0.0210.219 MEM0777 0.786 0.019 0.195 MEM0778 0.813 0.016 0.171 MEM0779 0.8390.014 0.147 MEM0780 0.866 0.012 0.123 MEM0781 0.892 0.009 0.098 MEM07820.919 0.007 0.074 MEM0783 0.946 0.005 0.049 MEM0784 0.973 0.002 0.025MEM0785 0.558 0.078 0.364 MEM0007 0.584 0.074 0.343 MEM0786 0.609 0.0690.322 MEM0787 0.634 0.065 0.301 MEM0013 0.660 0.060 0.280 MEM0788 0.6850.056 0.259 MEM0789 0.711 0.051 0.238 MEM0790 0.737 0.046 0.217 MEM07910.763 0.042 0.195 MEM0792 0.789 0.037 0.174 MEM0793 0.815 0.033 0.152MEM0794 0.841 0.028 0.131 MEM0795 0.867 0.023 0.109 MEM0796 0.894 0.0190.088 MEM0797 0.920 0.014 0.066 MEM0798 0.947 0.009 0.044 MEM0799 0.9730.005 0.022

TABLE 62 MCT T80:G ID Water Oil Surfactant 4 to 1 MEM0800 0.481 0.0450.473 MEM0801 0.506 0.043 0.451 MEM0802 0.531 0.041 0.428 MEM0803 0.5560.039 0.405 MEM0804 0.582 0.037 0.382 MEM0805 0.607 0.034 0.358 MEM08060.633 0.032 0.335 MEM0807 0.658 0.030 0.312 MEM0808 0.684 0.028 0.288MEM0809 0.710 0.025 0.265 MEM0810 0.736 0.023 0.241 MEM0811 0.762 0.0210.218 MEM0812 0.788 0.019 0.194 MEM0813 0.814 0.016 0.170 MEM0814 0.8400.014 0.146 MEM0815 0.867 0.012 0.122 MEM0816 0.893 0.009 0.098 MEM08170.920 0.007 0.073 MEM0818 0.946 0.005 0.049 MEM0819 0.973 0.002 0.025MEM0039 0.560 0.078 0.362 MEM0820 0.585 0.074 0.341 MEM0821 0.610 0.0690.320 MEM0822 0.636 0.065 0.299 MEM0823 0.661 0.060 0.278 MEM0040 0.6870.056 0.257 MEM0824 0.713 0.051 0.236 MEM0825 0.738 0.047 0.215 MEM08260.764 0.042 0.194 MEM0827 0.790 0.037 0.173 MEM0828 0.816 0.033 0.151MEM0829 0.842 0.028 0.130 MEM0830 0.868 0.023 0.108 MEM0831 0.894 0.0190.087 MEM0832 0.921 0.014 0.065 MEM0833 0.947 0.009 0.044 MEM0834 0.9730.005 0.022MEM0800-MEM0802 were unstable.

TABLE 63 MCT T80:G ID Water Oil Surfactant 5 to 1 MEM0835 0.482 0.0460.472 MEM0836 0.507 0.043 0.449 MEM0837 0.532 0.041 0.426 MEM0838 0.5580.039 0.403 MEM0839 0.583 0.037 0.380 MEM0840 0.608 0.034 0.357 MEM08410.634 0.032 0.334 MEM0842 0.659 0.030 0.311 MEM0843 0.685 0.028 0.287MEM0844 0.711 0.025 0.264 MEM0845 0.736 0.023 0.240 MEM0846 0.762 0.0210.217 MEM0847 0.788 0.019 0.193 MEM0848 0.815 0.016 0.169 MEM0849 0.8410.014 0.145 MEM0850 0.867 0.012 0.121 MEM0851 0.893 0.009 0.097 MEM08520.920 0.007 0.073 MEM0853 0.947 0.005 0.049 MEM0854 0.973 0.002 0.024MEM0855 0.561 0.078 0.361 MEM0856 0.586 0.074 0.340 MEM0857 0.611 0.0690.319 MEM0858 0.637 0.065 0.298 MEM0859 0.662 0.060 0.277 MEM0860 0.6880.056 0.256 MEM0861 0.713 0.051 0.235 MEM0862 0.739 0.047 0.214 MEM08630.765 0.042 0.193 MEM0864 0.791 0.037 0.172 MEM0865 0.817 0.033 0.151MEM0866 0.843 0.028 0.129 MEM0867 0.869 0.023 0.108 MEM0868 0.895 0.0190.086 MEM0869 0.921 0.014 0.065 MEM0870 0.947 0.009 0.043 MEM0871 0.9740.005 0.022MEM0835-MEM0838 were unstable.

TABLE 64 MCT T80:TriAc ID Water Oil Surfactant 1 to 1 MEM0947 0.4780.045 0.477 MEM0948 0.503 0.043 0.454 MEM0949 0.528 0.041 0.431 MEM00210.553 0.039 0.408 MEM0950 0.579 0.036 0.385 MEM0951 0.604 0.034 0.361MEM0952 0.630 0.032 0.338 MEM0953 0.656 0.030 0.315 MEM0954 0.681 0.0280.291 MEM0955 0.707 0.025 0.267 MEM0956 0.733 0.023 0.244 MEM0957 0.7590.021 0.220 MEM0958 0.786 0.019 0.196 MEM0959 0.812 0.016 0.172 MEM09600.839 0.014 0.148 MEM0961 0.865 0.012 0.123 MEM0962 0.892 0.009 0.099MEM0963 0.919 0.007 0.074 MEM0964 0.946 0.005 0.050 MEM0965 0.973 0.0020.025

TABLE 65 MCT T80:TriAc ID Water Oil Surfactant 2 to 1 MEM0966 0.4820.046 0.473 MEM0009 0.507 0.043 0.450 MEM0967 0.532 0.041 0.427 MEM00150.557 0.039 0.404 MEM0968 0.582 0.037 0.381 MEM0969 0.608 0.034 0.358MEM0970 0.633 0.032 0.335 MEM0971 0.659 0.030 0.311 MEM0972 0.684 0.0280.288 MEM0973 0.710 0.025 0.265 MEM0974 0.736 0.023 0.241 MEM0975 0.7620.021 0.217 MEM0976 0.788 0.019 0.193 MEM0977 0.893 0.009 0.097 MEM09780.920 0.007 0.073 MEM0979 0.946 0.005 0.049 MEM0980 0.973 0.002 0.025

TABLE 66 MCT T80:TriAc ID Water Oil Surfactant 3 to 1 MEM0981 0.4830.046 0.471 MEM0982 0.508 0.043 0.448 MEM0983 0.533 0.041 0.425 MEM09840.559 0.039 0.402 MEM0985 0.584 0.037 0.379 MEM0986 0.609 0.035 0.356MEM0987 0.635 0.032 0.333 MEM0988 0.660 0.030 0.310 MEM0989 0.686 0.0280.287 MEM0990 0.711 0.026 0.263 MEM0991 0.737 0.023 0.240 MEM0992 0.9200.007 0.073 MEM0993 0.947 0.005 0.049 MEM0994 0.973 0.002 0.024

TABLE 67 MCT T80:TriAc ID Water Oil Surfactant 4 to 1 MEM0995 0.4840.046 0.470 MEM0996 0.509 0.044 0.447 MEM0997 0.534 0.041 0.424 MEM09980.559 0.039 0.401 MEM0999 0.585 0.037 0.378 MEM1000 0.610 0.035 0.355MEM1001 0.635 0.032 0.332 MEM1002 0.661 0.030 0.309

TABLE 68 MCT T80:TriAc ID Water Oil Surfactant 5 to 1 MEM1003 0.4850.046 0.469 MEM1004 0.510 0.044 0.447 MEM1005 0.535 0.041 0.424 MEM10060.560 0.039 0.401 MEM1007 0.636 0.032 0.332 MEM1008 0.662 0.030 0.308

Example 5 Comparison with Nanoemulsion

MSH-1001, a proprietary novel, highly insoluble small molecule, is anATP-sensitive K channel opener that has been shown to reduce intraocularpressure.

Eleven different microemulsions and one nanoemulsion comprising varyingspecified amounts of MSH-1001 were prepared. Nanoemulsion ED-002comprises 8 percent (w/w) castor oil, 2.2 percent (w/w) glycerin, 2percent (w/w) Pluronic F68, 1 percent (w/w) soybean lecithin, 0.002percent (w/w) alpha-tocopherol, and 85.8 percent (w/w) 1%carboxymethylcellulose (CMC)/deionized water. Compositions of themicroemulsions used in this example are provided in Table 69.

TABLE 69 Sur- Co- % % Sur- MSH- ID factant Surfactant IPM factant 1001Viscosity ED-007 3:1 Crem PG 1.7 18.6 0.1% 30.8 ER-008 4:1 T80 PG 1.718.7 0.1% 29.1 ED-009 4:1 T80 PG 5.9 29.9 0.1% 29.7 ED-010 2:1 Crem T201.7 19.3 0.1% 28.2 ED-011 3:1 Crem T20 1.7 19.3 0.1% 31.7 ED-012 3:1Crem Triacetin 1.4 18.6 0.1% 28.9 ED-013 3:1 Crem Triacetin 2.4 31.30.3% 20.5 ED-014 4:1 Crem PG 2.5 27.9 0.3% 19.9 ED-015 3:1 T80 T20 3.039 0.3% 458.9 ED-016 3:1 Crem PG 2.5 27.8 0.3% 15.6 ED-017 3:1 Crem PG3.3 37 0.3% 185.7 Crem = cremophor; PG = propylene glycol; T20 = Tween20; T80 = Tween 80

Quantification of MSH-1001 in rabbit aqueous humor (AH) at 1 hourfollowing administration of a single 60 μL eyedrop was performed usingLC-MS/MS.

Representative results are shown in FIG. 3. Following topicaladministration of the various eyedrops it was observed that a 0.5%MSH-1001 microemulsion delivered the same drug levels to the aqueoushumor as a 3% nanoemulsion and the 10% micronized suspension.

As shown in FIG. 3. MSH-1001 can be formulated into opticallytransparent and thermodynamically stable microemulsion eyedrops. Theseeyedrops, while having two orders of magnitude lower concentrations ofthe active ingredient, have demonstrated the ability to deliver the sameconcentration to the aqueous humor as more traditional eyedropformulations. These results indicate that this microemulsion eyedropformulation platform technology can be applied to increase oculardelivery of other lipophilic active pharmaceutical ingredients.

Example 6 Microemulsion Droplet Size

Representative microemulsions were characterized in terms of dropletsize of the emulsions. FIG. 4 shows the results of this analysis. Thesize distribution is plotted using a whisker plot, where the higher andlower extremes represent the d90 and d10 size distribution. D90 and d10exclude the highest 10% and lowest 10% of the particle distribution,respectively. As can be observed from FIG. 4, there is variability inthe d90 to d10 distribution. Most of the formulations tested had ad90:d10 ratio of about 2. The same can be said for the spread in FIG. 5,which is a comparison of the size of select formulations measured on day1 and day 14.

Example 7 Microemulsion Formulations of Fenofibrate

In this example the ability of fenofibrate to form microemulsions inisopropyl myristate (IPM) was evaluated. Of 45 formulations of isopropylmyristate initially screened, 20 were identified that were compatiblewith 0.5% fenofibrate. Table 70 shows representative formulations madewith IPM and Tween 80 (T80) as surfactant and propanediol (P) asco-surfactant. For comparison, formulations were also made with Tween 20(T20) as the surfactant and Tween 80 (T80) as the co-surfactant. In thislatter system 6 out of 15 screened formulations formed microemulsionswith IPM (Table 71).

TABLE 70 Isopropyl Myristate (IPM) Microemulsions of 0.5% FenofibrateOil Surfactant MEM Water IPM T80 P MEM0401 0.592 0.034 0.3000 0.0750MEM0402 0.617 0.031 0.2820 0.0704 MEM0403 0.642 0.029 0.2620 0.0656MEM0409 0.592 0.034 0.3125 0.0625 MEM0410 0.617 0.031 0.2933 0.0587MEM0381 0.492 0.042 0.3500 0.1165 MEM0382 0.517 0.040 0.3320 0.1108MEM0383 0.542 0.038 0.3150 0.1050 MEM0384 0.567 0.036 0.2980 0.0992MEM0385 0.592 0.034 0.2810 0.0935 MEM0386 0.617 0.031 0.2630 0.0878MEM0387 0.642 0.029 0.2460 0.0820 MEM0375 0.492 0.042 0.3110 0.1553MEM0376 0.517 0.040 0.2950 0.1477 MEM0377 0.542 0.038 0.2800 0.1400

TABLE 71 Additional Isopropyl Myristate (IPM) Microemulsions of 0.5%Fenofibrate Oil Surfactant MEM Water IPM T20 T80 MEM0042 0.498 0.0380.232 0.232 MEM0043 0.523 0.036 0.220 0.220 MEM0044 0.548 0.035 0.2090.209 MEM0045 0.574 0.033 0.197 0.197 MEM0053 0.687 0.025 0.057 0.230MEM0054 0.713 0.023 0.053 0.211

Example 8 Stability of Microemulsion Formulations of Fenofibrate

Microemulsion MEM0043 containing 0.5% fenofibrate was prepared as inExample 7 and stored at room temperature for over one year. Droplet sizewas assessed as in Example 6 on days 1, 14, and 379. Results are shownin FIG. 6. One-way ANOVA analysis showed there is no significantdifference among the three groups (p >0.05).

Example 9 In Vivo Delivery of Fenofibrate and Fenofibric Acid to Mice

C57BL/6 mice were administered various formulations of fenofibrate viavarious routes of administration, and then ocular concentrations offenofibrate and fenofibric acid were determined using LC/MS. For fiveconsecutive days, fenofibrate drops were given QID in three differentnanoemulsions NEM-001, NEM-002, and NEM-003 (each prepared with 0.5% and3.0% fenofibrate); a UID oral administration at a concentration of 200mg/kg; and three microemulsion formulations (MEM0043, MEM0044, andMEM0045) at 0.5% fenofibrate. Eyes were then enucleated and whole eye(pigmented epithelium, cornea, retina, sclera; aka PECRS) washomogenized and concentrations of fenofibrate and fenofibric acid weremeasured. Results of LC/MS measurements indicated that the threemicroemulsions delivered similar amounts of fenofibric acid, and morefenofibrate was measured with the 0.5% microemulsions compared to allthree 0.5% nanoemulsions. The nanoemulsions exhibited significantcreaming and are not considered to be stable for more than a week.

Example 10 In Vivo Delivery of Fenofibrate and Fenofibric Acid to Rats

Brown Norway rats were administered fenofibrate eye drops, either as ananoemulsion (NEM-001) with 3% fenofibrate or as a microemulsion(MEM0043) with 0.5% fenofibrate, QID for 19 days. Eyes were thenenucleated and the retina was separated from the PECS (pigmentedepithelium, cornea, and sclera) and measured separately, as was thevitreous. PECS and retina were homogenized and concentrations offenofibrate and fenofibric acid were measured using LC/MS. Results(Table 72) showed that the concentration of fenofibrate in both theretina and PECS was significantly higher with the 3% nanoemulsion thanwith the 0.5% microemulsion. However, the concentration of fenofibricacid was not significantly different between the two formulations asmeasured with Student's T test.

TABLE 72 LC/MS Quantification of Ocular Concentrations of Fenofibrateand Fenofibric Acid Vitreous PECS Retina Fenofibric FenofibrateFenofibric Fenofibrate Fenofibric Fenofibrate Acid ID Treatment (ng/g)Acid (ng/g) (ng/g) Acid (ng/g) (ng/mL) (ng/L) 1 NEM-001 3.0% 141.6 4.380.58 17.60 159.00 2.07 2 NEM-001 3.0% 3368.00 9.12 0.26 8.51 0.40 10.803 NEM-001 3.0% 72.8 4.17 0.31 2.93 0.67 0.76 4 NEM-001 3.0% 9.84 4.480.09 0.00 0.68 1.00 5 NEM-001 3.0% 3.70 10.56 457.71 3.84 0.39 1.55 6NEM-001 3.0% 4.19 5.16 99.43 6.46 2.21 4.74 7 NEM-001 3.0% 3.07 4.6618.11 3.54 0.77 0.71 8 NEM-001 3.0% 259.20 0.00 6.40 2.94 2.00 0.00 9MEM0043 2.21 0.00 2.37 4.37 0.52 2.80 0.5% 10 MEM0043 3.57 10.72 4.287.83 0.75 12.80 0.5% 11 MEM0043 4.62 0.00 1.27 7.83 0.70 0.61 0.5% 12MEM0043 6.29 0.00 0.00 5.16 15.90 3.03 0.5% 13 MEM0043 34.32 0.00 6.517.09 0.33 8.99 0.5% 14 MEM0043 10.56 8.64 1.05 5.77 1440.00 6.53 0.5% 15MEM0043 4.78 11.36 0.00 8.34 24.10 11.00 0.5% 16 MEM0043 6.15 13.68 2.238.63 2.06 3.83 0.5% 17 MEM0043 3.76 8.96 1.46 3.66 0.56 4.85 0.5% 18MEM0043 5.34 4.34 1.14 2.82 0.11 0.50 0.5% 19 MEM0043 5.34 16.80 1.3110.23 0.97 4.27 0.5% 20 MEM0043 31.60 11.92 0.47 12.29 0.43 1.51 0.5%

Example 11 In Vivo Delivery of Fenofibrate and Fenofibric Acid toRabbits

Dutch belted rabbits were administered fenofibrate eye drops QID for 5days. Two nanoemulsions (NEM-001 and NEM-002) with 3% fenofibrate andtwo microemulsion (MEM0043 and MEM0044) with 0.5% fenofibrate wereadministered for this study. Eyes were then enucleated and the tissuewas dissected (retina, retinal pigment epithelium (RPE), vitreous humor,aqueous humor, sclera, iris, cornea, and conjunctiva). The tissues werehomogenized and concentrations of fenofibrate and fenofibric acid weremeasured using LC/MS. Table 73 shows the results of these LC/MSmeasurements, and FIG. 7 shows the concentrations of fenofibrate andfenofibric acid in the retina and RPE for all four formulations.Surprisingly, in both of these posterior tissues the 0.5% microemulsionshad higher drug concentration than the 3.0% nanoemulsions. In the retinathere was virtually no fenofibrate or fenofibric acid in eyes that weredosed with either nanoemulsion. In eyes that were dosed withmicroemulsion, there were fairly consistent amounts of fenofibrate butvery little fenofibric acid in the retina samples. In the RPE muchhigher concentration of fenofibric acid could be observed in all fourformulations, while fenofibrate could not be detected at all in thenanoemulsions, and MEM0043 had higher fenofibrate and fenofibric acidthan MEM0044. In the anterior corneal tissue large concentrations offenofibric acid were detected in the microemulsion formulations, whilethe concentration of fenofibric acid measured in the nanoemulsionformulations was almost two orders of magnitude lower.

The results shown in FIG. 7 are surprising because they show verydifferent drug dispositions within eye tissue depending on formulation,notwithstanding the similarity in particle size for the microemulsionformulations (137±40.3 nm) and the nanoemulsion formulations (205±74.9nm).

TABLE 73 LC/MS Quantification of Ocular Concentrations of Fenofibrateand Fenofibric Acid Tissue Type: Retina RPE Treatment FenofibrateFenofibrate Fenofibric Fenofibrate Fenofibric Animal Number GroupConcentration (ng/g) Acid (ng/g) (ng/g) Acid (ng/g) 1154R NEM001 3.0%0.00 0.00 0.00 12.30 1154L NEM001 3.0% 0.00 0.00 0.00 12.90 1155R NEM0013.0% 113.10 0.00 0.00 9.70 1155L NEM001 3.0% 0.90 0.00 0.00 9.30 1160RNEM002 3.0% 0.00 0.00 0.00 11.50 1160L NEM002 3.0% 0.00 0.00 0.00 3.001161R NEM002 3.0% 0.00 0.00 0.00 5.70 1161L NEM002 3.0% 0.00 0.00 0.008.70 1156R MEM0043 0.5% 8.20 2.80 1960.00 22.10 1156L MEM0043 0.5% 6.208.20 53.80 62.90 1157R MEM0043 0.5% 6.30 0.00 7.70 25.50 1157L MEM00430.5% 6.10 0.00 9.70 19.20 1158R MEM0044 0.5% 5.90 0.00 5.30 11.60 1158LMEM0044 0.5% 5.00 0.00 5.00 8.00 1159R MEM0044 0.5% 5.60 0.00 6.80 12.901159L MEM0044 0.5% 4.70 0.00 4.80 6.90 Tissue Type: Vitreous AqueousTreatment Fenofibrate Fenofibrate Fenofibric Fenofibrate FenofibricAnimal Number Group Concentration (ng/mL) Acid (ng/mL) (ng/mL) Acid(ng/mL) 1154R NEM001 3.0% 0.00 0.00 0.00 5.53 1154L NEM001 3.0% 40.500.00 0.00 2.78 1155R NEM001 3.0% 0.00 0.00 0.00 2.15 1155L NEM001 3.0%0.00 0.00 0.00 1.52 1160R NEM002 3.0% 0.00 0.00 0.00 5.14 1160L NEM0023.0% 0.00 0.62 0.00 6.22 1161R NEM002 3.0% 0.00 0.00 0.00 3.56 1161LNEM002 3.0% 0.00 0.00 0.00 26.60 1156R MEM0043 0.5% 0.67 0.00 0.66 7.411156L MEM0043 0.5% 0.55 0.00 1.01 8.63 1157R MEM0043 0.5% 0.50 0.00 0.857.05 1157L MEM0043 0.5% 0.71 0.00 0.67 4.33 1158R MEM0044 0.5% 0.62 0.000.55 6.75 1158L MEM0044 0.5% 0.71 0.00 0.82 3.42 1159R MEM0044 0.5% 0.680.00 0.78 5.10 1159L MEM0044 0.5% 0.75 0.00 0.78 2.22 Tissue Type:Sclera Iris Treatment Fenofibrate Fenofibrate Fenofibric FenofibrateFenofibric Animal Number Group Concentration (ng/g) Acid (ng/g) (ng/g)Acid (ng/g) 1154R NEM001 3.0% 0.00 36.10 0.00 0.00 1154L NEM001 3.0%0.00 19.00 0.00 0.00 1155R NEM001 3.0% 0.00 9.90 0.00 1.20 1155L NEM0013.0% 0.00 21.50 0.00 2.70 1160R NEM002 3.0% 0.00 20.10 81.10 0.00 1160LNEM002 3.0% 0.00 25.10 0.00 0.00 1161R NEM002 3.0% 0.00 14.40 223.400.00 1161L NEM002 3.0% 0.00 9.60 0.00 0.00 1156R MEM0043 0.5% 35.7081.70 273.10 164.60 1156L MEM0043 0.5% 25.90 92.60 13.80 30.30 1157RMEM0043 0.5% 16.20 73.70 13.70 0.70 1157L MEM0043 0.5% 41.10 56.90 4.502.40 1158R MEM0044 0.5% 6.90 54.70 4.70 0.40 1158L MEM0044 0.5% 9.0054.50 3.40 0.00 1159R MEM0044 0.5% 21.60 80.60 2.80 1.20 1159L MEM00440.5% 15.50 72.00 3.10 1.20 Tissue Type: Cornea Conjunctiva TreatmentFenofibrate Fenofibrate Fenofibric Fenofibrate Fenofibric Animal NumberGroup Concentration (ng/g) Acid (ng/g) (ng/g) Acid (ng/g) 1154R NEM0013.0% 0.00 256.60 0.20 161.10 1154L NEM001 3.0% 0.00 205.70 0.00 110.901155R NEM001 3.0% 0.00 76.60 0.00 49.10 1155L NEM001 3.0% 0.00 102.300.00 49.90 1160R NEM002 3.0% 0.00 98.30 0.00 85.10 1160L NEM002 3.0%0.00 173.70 0.00 81.10 1161R NEM002 3.0% 0.00 113.70 0.00 42.30 1161LNEM002 3.0% 0.00 70.30 1931.40 23.10 1156R MEM0043 0.5% 5.30 7657.104.20 278.30 1156L MEM0043 0.5% 8.60 8857.10 7.40 282.90 1157R MEM00430.5% 7.80 8628.60 9.10 406.30 1157L MEM0043 0.5% 5.60 10685.70 4.00242.90 1158R MEM0044 0.5% 4.80 10342.90 4.90 407.40 1158L MEM0044 0.5%14.00 11714.30 4.30 278.90 1159R MEM0044 0.5% 12.90 15314.30 3.40 361.701159L MEM0044 0.5% 6.20 13257.10 6.70 258.90

Example 12 In Vivo Efficacy of Fenofibrate Microemulsion Formulation

To show that the levels of fenofibrate and fenofibric acid aretherapeutically relevant we used a laser-induced choroidalneovascularization rodent model. The rats used in this study were thesame animals used in Example 10. On Day 1, 3 subchoroidal neovascularlesions/wounds were created in both eyes of 8-week old female BrownNorway rats at the 3 o'clock, 6 o'clock, and 9 o'clock positions. On Day2, cohorts of 5 rats were randomly assigned to treatment groups andreceived 25 μL eyedrop applications of 0.0% (vehicle), 0.5% MEM0043, or3% NEM-001 Q.I.D. for 19 days. On Day 22, in vivo fluoresceinangiography was performed on all rats utilizing intraperitonealadministration of fluorescein sodium and funduscope imaging coupled witha 488 nm bandpass filter. Both fluorescent and color funduscopic imageswere captured for each eye, and lesion areas were hand-quantified bymasked observers. FIG. 8 shows representative results of thequantification of the leakage measurements. The leakage in both thenanoemulsion and the microemulsion formulations were significantly(p<0.001) reduced compared to vehicle.

Example 13 Synthesis of CLT-005

CLT-005 can be synthesized as shown in Scheme 1 or as shown in Scheme 2:

EQUIVALENTS

Having now fully described the present invention in some detail by wayof illustration and example for purposes of clarity of understanding, itwill be obvious to one of ordinary skill in the art that the same can beperformed by modifying or changing the invention within a wide andequivalent range of conditions, formulations and other parameterswithout affecting the scope of the invention or any specific embodimentthereof, and that such modifications or changes are intended to beencompassed within the scope of the appended claims.

INCORPORATION BY REFERENCE

All patents and published patent applications mentioned in thedescription above are incorporated by reference herein in theirentirety.

1-18. (canceled)
 19. A method of treating a disease of the posteriorsegment of the eye, comprising: topically administering to an eye of asubject in need thereof a composition comprising an oil-in-watermicroemulsion comprising (i) an oil selected from the group consistingof isopropyl myristate, isopropyl palmitate, and medium chaintriglycerides; (ii) a pair of surfactants selected from the groupconsisting of two polysorbates, a polysorbate and propylene glycol, apolysorbate and glycerol, a polysorbate and 1,2,3-triacetoxypropane,polyethoxylated castor oil and 1,2,3-triacetoxypropane, andpolyethoxylated castor oil and propylene glycol; (iii) water; and (iv) atherapeutically effective amount, for treating a disease of theposterior segment of the eye, of a lipophilic active pharmaceuticalingredient (API), wherein: the API represents about 0.01 to about 5percent (w/v) of the composition; the water represents 50 to about 95percent (w/w) of the composition; the oil and surfactants representsubstantially all of the remainder of the composition; the ratio ofpercent (w/w) total surfactant to percent (w/w) oil is at least about10:1; and the composition is formulated for topical administration tothe eye.
 20. The method of claim 19, wherein the lipophilic API isselected from the group consisting of adaprolol maleate, cyclosporine A,fenofibrate, fenofibric acid, indomethacin, miconazole, pilocarpine,piroxicam, and Δ⁸-THC.
 21. The method of claim 19, wherein thelipophilic API is fenofibrate.
 22. The method of claim 19, wherein thelipophilic API is fenofibric acid.
 23. The method of claim 19, whereinthe lipophilic API is represented by


24. The method of claim 19, wherein the disease of the posterior segmentof the eye is characterized by inflammation, neovascularization,vascular leakage, fibrosis, or any combination thereof.
 25. The methodof claim 19, wherein the disease of the posterior segment of the eye isselected from the group consisting of: age-related macular degeneration,diabetic retinopathy, posterior uveitis, retinal edema, macular edema,and retinal vein occlusion.
 26. The method of claim 19, wherein thedisease of the posterior segment of the eye is age-related maculardegeneration.
 27. The method of claim 19, wherein the disease of theposterior segment of the eye is diabetic retinopathy.
 28. (canceled) 29.(canceled)